E3 ligase family function and interaction

Abstract

Provided herein are methods of treating cancer, inflammatory diseases, and autoimmune diseases, and methods of modulating related phenotypes and expression levels, by targeting interactions between E3 ligases, E3-like proteins, and interacting partners thereof. Methods of identifying modulators of such interactions are also provided. Also provided herein are altered cell therapies comprising at least two members of a co-functional gene module.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 440,365, filed January 20, 2023, and Japanese Patent Application No. 2023-186191, filed October 31, 2023, the entire contents of which are incorporated herein by reference in their entirety.

[0003] Statement on Federally Funded Research

[0004] This invention was completed with government support from the National Human Genome Research Institute (NHGRI) Center for Excellence in Genome Sciences (CEGS) grant number 5RM1HGP706193-09 and the National Institutes of Health (NIH) Ruth L. Kirschstein National Research Service Award (NRSA) grant number 5F32AI138458 for an individual postdoctoral fellow (F32). The U.S. government holds certain rights to this invention. Technical Field

[0005] This article provides methods for treating cancer, inflammatory diseases, and autoimmune diseases by targeting the interactions between E3 ligases, E3-like proteins, and their interacting partners, as well as methods for regulating related phenotypes and expression levels. Methods for identifying regulators of such interactions are also provided. This article further provides cell therapies involving alterations to at least two members of a cofunctional gene module. Background Technology

[0006] The human genome encodes over 600 E3 ubiquitin ligases, which are responsible for catalyzing the binding of ubiquitin to substrates in virtually every biochemical pathway. Genome-wide association studies (GWAS) have shown that variants of E3 ligase genes are associated with numerous diseases, including inflammatory and autoimmune diseases. While previous research has indicated that certain E3 ligases are involved in the inflammatory response of dendritic cells to lipopolysaccharide (LPS), little is known about the roles of E3 ligases, E3-like proteins, interacting partner bodies, and their substrates in dendritic cells or other primary immune cells. Therefore, there is a need in the art to elucidate novel roles and relationships of E3 ligases and related genes in primary immune cells, as well as methods for modulating these newly discovered roles and relationships (e.g., to treat cancer, inflammatory diseases, or autoimmune diseases). Summary of the Invention

[0007] In one aspect, the present invention provides a method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering to the individual an effective amount of one, two, or all three of (a) LIM domain-binding protein 2 (Ldb2), ring finger protein 165 (Rnf165), and TNF receptor-associated factor 2 (Traf2) as a modulator of the interaction between (b) chemokine receptor type 7 (CCR7).

[0008] In some respects, the individual has cancer, and the modulator is an agent that reduces the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0009] In other respects, the individual suffers from an inflammatory disease or an autoimmune disease, and the modulator is an agent that increases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0010] In another aspect, the present invention provides a method for increasing the expression of chemokine receptor type 7 (CCR7) in antigen-presenting cells (APCs), the method comprising contacting the APC with an effective amount of an agent that reduces the expression and / or activity of one, two, or all three of LIM domain-binding protein 2 (Ldb2), ring finger protein 165 (Rnf165), and TNF receptor-associated factor 2 (Traf2).

[0011] In some respects, APC exists within an individual. In some respects, the individual has cancer.

[0012] In some respects, CCR7 expression in APC is increased by at least 10% compared to expression in the absence of the drug.

[0013] In another aspect, the present invention provides a method for increasing the migration of APCs to tumors and / or lymph nodes in an individual, the method comprising administering to the individual an effective amount of an agent that reduces the expression and / or activity of one, two, or all three of LIM domain-binding protein 2 (Ldb2), ring finger protein 165 (Rnf165), and TNF receptor-associated factor 2 (Traf2).

[0014] In some respects, the individual has cancer.

[0015] In some respects, the migration of APCs to tumors and / or lymph nodes in this individual was at least 10% greater than the migration in the absence of the drug.

[0016] In some respects, APCs are dendritic cells (DCs), macrophages, or glial cells. In other respects, glial cells are microglia, astrocytes, or oligodendrocytes. In still other respects, APCs are DCs.

[0017] In another aspect, the present invention provides a method for increasing T cell homing to tumors in an individual, the method comprising administering to the individual an effective amount of an agent that reduces the expression and / or activity of one, two, or all three of LIM domain-binding protein 2 (Ldb2), ring finger protein 165 (Rnf165), and TNF receptor-associated factor 2 (Traf2).

[0018] In some respects, T cell homing to the tumor increased by at least 10% in this individual compared to T cell homing in the absence of the drug.

[0019] In some cases, inflammatory or autoimmune diseases include neurodegenerative diseases, arthritis, allergies, eczema, fibrosis, asthma, lupus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In other cases, neurodegenerative diseases include multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD). In still other cases, inflammatory or autoimmune diseases include Crohn's disease.

[0020] In some respects, the agent is a protein hydrolysis-targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or an inhibitory nucleic acid.

[0021] In some respects, the inhibitory nucleic acid is ASO or siRNA.

[0022] In some respects, the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, a bispecific antibody, a linear antibody, scFv, scFab, a VH domain, or a VHH domain. In some respects, the antibody or its antigen-binding fragment binds to Ldb2, Rnf165, or Traf2. In some respects, the antibody or its antigen-binding fragment binds to CCR7. In some respects, the agent is a bispecific antibody containing an antigen-binding domain that targets the tumor microenvironment.

[0023] In some respects, the method further includes administering one or more additional agents to the individual or exposing the APC to one or more additional agents.

[0024] In some aspects, the method further includes administering one or more agents to the individual or exposing the APC to one or more agents, which modulate Akt1, Ankfy1, Apc, Arpc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbxl13, Fbxo28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, M Expressions of one or more of the following: lst8, Mtor, Nosip, Paf1, Pik3r4, Pparg, Ppp2r2a, Ppp2r2d, Preb, Rbbp4, Rbbp5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13, Sec31a, Smad2, Syvn1, Taf5l, Traf2, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1, and Zbtb11.

[0025] In another aspect, the present invention provides a kit comprising a modulator of the interaction between (a) one, two, or all three of Ldb2, Rnf165, and Traf2 and (b) CCR7, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease according to any of the methods provided herein. In some aspects, the kit includes a packaging insert containing instructions for administering the modulator to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

[0026] In another aspect, the present invention provides a method for monitoring the response of an individual suffering from cancer, an inflammatory disease, or an autoimmune disease to treatment with a modulator of the interaction between (a) one, two, or all three of Ldb2, Rnf165, and Traf2 and (b) CCR7, the method comprising: (i) determining the expression levels of one or more of Ldb2, Rnf165, and Traf2 in a biological sample obtained from the individual at a time point following administration of the modulator; and (ii) comparing the expression levels of one or more genes in the biological sample to a reference level, thereby monitoring the individual's response to treatment with the modulator.

[0027] In some respects, the reference level is selected from the group consisting of: (i) the expression level of one or more genes in a biological sample obtained from an individual prior to the administration of the regulator; (ii) the expression level of one or more genes in a reference population; (iii) a pre-specified expression level for one or more genes; or (iv) the expression level of one or more genes in a biological sample obtained from an individual at a previous time point, wherein the previous time point is after the administration of the regulator.

[0028] In some respects, the individual has cancer, the expression levels of one or more genes in a biological sample obtained from the individual are increased relative to a reference level, and the method further includes administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that reduces the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0029] In some respects, the individual suffers from an inflammatory disease or an autoimmune disease, the expression levels of one or more genes in a biological sample obtained from the individual are reduced relative to a reference level, and the method further includes administering one or more additional doses of the modulator to the individual; wherein the modulator is an agent that increases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0030] In another aspect, the present invention provides a method for treating an individual with cancer, inflammatory disease, autoimmune disease, or infectious disease, the method comprising administering to the individual an effective amount of: (a) an agent that reduces the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) an agent that reduces the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) an agent that increases the expression and / or activity of death-inducing termination factor 1 (Dido1).

[0031] In some respects, autoimmune diseases are associated with a reduced proportion of migratory dendritic cells (mDCs).

[0032] In some respects, individuals have loss-of-function mutations in Dido1.

[0033] In another aspect, the present invention provides a method for treating an individual with an inflammatory disease, an autoimmune disease, or an infectious disease, the method comprising administering to the individual an effective amount of: (a) an agent that increases the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) an agent that increases the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) an agent that decreases the expression and / or activity of death-inducing termination factor 1 (Dido1).

[0034] In another aspect, the present invention provides a method for increasing the proportion of migratory dendritic cells (mDCs) in an individual, the method comprising administering to the individual an effective amount of: (a) an agent that reduces the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) an agent that reduces the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) an agent that increases the expression and / or activity of death-inducing termination factor 1 (Dido1).

[0035] In some respects, this proportion refers to the proportion of a tumor or tissue in that individual.

[0036] In some respects, the proportion of mDC in this individual is increased by at least 10% relative to the proportion in the absence of the drug.

[0037] In another aspect, the present invention provides a method for increasing an individual's antitumor immunity, the method comprising administering to the individual an effective amount of: (a) an agent that reduces the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) an agent that reduces the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) an agent that increases the expression and / or activity of death-inducing termination factor 1 (Dido1).

[0038] In some respects, the individual's antitumor immunity increased by at least 10% compared to the antitumor immunity in the absence of the drug.

[0039] In another aspect, the present invention provides a method for reducing the proportion of migratory dendritic cells (mDCs) in an individual, the method comprising administering to the individual an effective amount of: (a) an agent that increases the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) an agent that increases the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) an agent that decreases the expression and / or activity of death-inducing elimination factor 1 (Dido1).

[0040] In some respects, this proportion refers to the proportion of a tumor or tissue in that individual.

[0041] In some respects, the proportion of mDC in this individual is reduced by at least 10% relative to the proportion in the absence of the drug.

[0042] In another aspect, the present invention provides a method for reducing the autoimmune activity of an individual, the method comprising administering to the individual an effective amount of: (a) an agent that increases the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) an agent that increases the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) an agent that decreases the expression and / or activity of death-inducing termination factor 1 (Dido1).

[0043] In some respects, the individual's autoimmune activity was reduced by at least 10% compared to antitumor immunity in the absence of the drug.

[0044] In some cases, inflammatory or autoimmune diseases include neurodegenerative diseases, arthritis, allergies, eczema, fibrosis, asthma, lupus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In other cases, neurodegenerative diseases include MS, AD, ALS, or PD.

[0045] In some respects, the agent is a protein hydrolysis-targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or an inhibitory nucleic acid.

[0046] In some respects, the inhibitory nucleic acid is ASO or siRNA.

[0047] In some respects, the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bisomatic antibody, linear antibody, scFv, scFab, VH domain or VHH domain.

[0048] In some respects, antibodies or their antigen-binding fragments bind to Cebpb, Traf2, and / or Dido1.

[0049] In some respects, the method further includes administering one or more additional agents to the individual.

[0050] In some aspects, the method further includes administering to an individual one or more agents that regulate the expression of one or more of the following: (a) Ago2, Ahr, Anapc13, Bach1, Baz1a, Bid, Bptf, Brca1, Brwd3, Btbd1, Cblc, Ccnf, Cdc27, Cntn4, Copa, Copb2, Coro1a, Cpne9, Cul4b, Ddb1, E4f1, Ecel1, Fbxl14, Fbxl5, Fbxo11, Fbxo42, Fzr1, Gemin5, Gm10697, Gm9117, Gtf2h2, Gtf3c1, Hdac4, Hectd1, Ift122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23 , Klhl3, Kmt2b, LOC100861784, Lrr1, Lrrc41, Map3k7, Mdm4, Mib1, Mkrn1, Mnat1, Naca, Nsm af, Ogt, Pa2g4, Pcif1, Ppp1r11, Prc1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah 2. Taf3, Tdpoz2, Tmem183a, Tnfsf11, Tradd, Traf3ip2, Trim35, Trim7, Tssc1, Ttc3, Ube2n , Ufl1, Unkl, Upf1, Vdr, Wdhd1, Wdr48, Wdr95, Wwp1, Ybx1, Zbtb14, Zbtb49, Zbtb7a and Zmiz1;and / or (b) Akt1, Ankfy1, Apc, Arpc1b, Birc2, Bmi1, Bub3, Cacybp, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbxl13, Fbxo28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, Mlst8, Mtor, Nosip, Pa f1, Pik3r4, Pparg, Ppp2r2a, Ppp2r2d, Preb, Rbbp4, Rbbp5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13 , Sec31a, Smad2, Syvn1, Taf5l, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1 and Zbtb11. ;

[0051] In another aspect, the present invention provides a kit comprising: (a) an agent that reduces the expression and / or activity of Cebpb; (b) an agent that reduces the expression and / or activity of Traf2; and / or (c) an agent that increases the expression and / or activity of Dido1, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease according to any of the methods provided herein. In some aspects, the kit includes a packaging insert containing instructions for administering the agent to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

[0052] In another aspect, the present invention provides a kit comprising: (a) an agent that increases the expression and / or activity of Cebpb; (b) an agent that increases the expression and / or activity of Traf2; and / or (c) an agent that decreases the expression and / or activity of Dido1, the kit being used to treat an individual suffering from an inflammatory disease or an autoimmune disease according to any of the methods provided herein. In some aspects, the kit includes a packaging insert containing instructions for administering the agent to an individual suffering from an inflammatory disease or an autoimmune disease.

[0053] In another aspect, the present invention provides a method for monitoring the response of an individual suffering from cancer, inflammatory disease, autoimmune disease, or infectious disease to treatment with an agent that (a) reduces the expression and / or activity of Cebpb; (b) reduces the expression and / or activity of Traf2; and / or (c) increases the expression and / or activity of Dido1, the method comprising: (i) determining the expression levels of one or more of Cebpb, Traf2, and Dido1 in a biological sample obtained from the individual at a time point following administration of the agent; and (ii) comparing the expression levels of one or more genes in the biological sample to a reference level, thereby monitoring the individual's response to treatment with the agent.

[0054] In another aspect, the present invention provides a method for monitoring the response of an individual suffering from an inflammatory disease, an autoimmune disease, or an infectious disease to treatment with an agent that (a) increases the expression and / or activity of Cebpb; (b) increases the expression and / or activity of Traf2; and / or (c) decreases the expression and / or activity of Dido1, the method comprising: (i) determining the expression levels of one or more of Cebpb, Traf2, and Dido1 in a biological sample obtained from the individual at a time point following administration of the agent; and (ii) comparing the expression levels of one or more genes in the biological sample to a reference level, thereby monitoring the individual's response to treatment with the agent.

[0055] In some respects, the reference level is selected from the group consisting of: (i) the expression level of one or more genes in a biological sample obtained from an individual prior to drug administration; (ii) the expression level of one or more genes in a reference population; (iii) a pre-specified expression level for one or more genes; or (iv) the expression level of one or more genes in a biological sample obtained from an individual at a previous time point, wherein the previous time point is after drug administration.

[0056] In some aspects, (a) the expression and / or activity of Cebpb in a biological sample obtained from the individual is increased relative to a reference level; (b) the expression and / or activity of Traf2 in a biological sample obtained from the individual is increased relative to a reference level; and / or (c) the expression and / or activity of Dido1 in a biological sample obtained from the individual is decreased relative to a reference level, and the method further includes administering one or more additional doses of an agent to the individual, wherein the agent decreases the expression and / or activity of Cebpb; decreases the expression and / or activity of Traf2; and / or increases the expression and / or activity of Dido1.

[0057] In some aspects, (a) the expression and / or activity of Cebpb in a biological sample obtained from the individual is reduced relative to a reference level; (b) the expression and / or activity of Traf2 in a biological sample obtained from the individual is reduced relative to a reference level; and / or (c) the expression and / or activity of Dido1 in a biological sample obtained from the individual is increased relative to a reference level, and the method further includes administering one or more additional doses of an agent to the individual, wherein the agent increases the expression and / or activity of Cebpb; increases the expression and / or activity of Traf2; and / or decreases the expression and / or activity of Dido1.

[0058] In another aspect, the present invention provides a method for treating an individual with cancer, inflammatory disease, or autoimmune disease, the method comprising administering to the individual an effective amount of a modulator of the interaction between (a) an F-box and WD repeat domain 11 (Fbxw11) and (b) nuclear factor κB subunit 1 (Nfkb1) or nuclear factor κB subunit 2 (Nfkb2).

[0059] In some respects, the individual has cancer, and the modulator is a drug that increases the expression and / or activity of Fbxw11.

[0060] In some respects, the individual suffers from an inflammatory disease or an autoimmune disease, and the modulator is an agent that reduces the expression and / or activity of Fbxw11.

[0061] In another aspect, the present invention provides a method for increasing the processing of Nfkb1 and / or Nfkb2 into an active form, the method comprising contacting cells capable of expressing Fbxw11 with an agent that increases the expression and / or activity of Fbxw11.

[0062] In some individuals, cells capable of expressing Fbxw11 exist. In other individuals, the individual may have cancer.

[0063] In some respects, the levels of Nfkb1 and / or Nfkb2 in their active forms are increased by at least 10% relative to the levels in the absence of the drug.

[0064] In another aspect, the present invention provides a method for reducing the processing of Nfkb1 and / or Nfkb2 into an active form, the method comprising contacting cells capable of expressing Fbxw11 with an agent that reduces the expression and / or activity of Fbxw11.

[0065] In some respects, cells capable of expressing Fbxw11 exist in individuals.

[0066] In some respects, individuals suffer from inflammatory diseases or autoimmune diseases.

[0067] In some respects, the levels of Nfkb1 and / or Nfkb2 in their active forms are reduced by at least 10% relative to the levels in the absence of the drug.

[0068] In another aspect, the present invention provides a method for increasing an immune response directed by Nfkb1 and / or Nfkb2 in an individual, the method comprising administering to the individual an effective amount of an agent that increases the expression and / or activity of Fbxw11.

[0069] In some respects, the individual has cancer.

[0070] In another aspect, the present invention provides a method for reducing an immune response directed by Nfkb1 and / or Nfkb2 in an individual, the method comprising administering to the individual an effective amount of an agent that reduces the expression and / or activity of Fbxw11.

[0071] In some respects, individuals suffer from inflammatory diseases or autoimmune diseases.

[0072] In some cases, inflammatory or autoimmune diseases include neurodegenerative diseases, arthritis, allergies, eczema, fibrosis, asthma, lupus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In other cases, neurodegenerative diseases include MS, AD, ALS, or PD.

[0073] In some respects, the agent is a proteolytic targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or a repressive nucleic acid. In some respects, the repressive nucleic acid is an ASO or siRNA.

[0074] In some respects, the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bisomatic antibody, linear antibody, scFv, scFab, VH domain or VHH domain.

[0075] In some respects, the antibody or its antigen-binding fragment binds to Fbxw11.

[0076] In some respects, the method further includes administering one or more additional agents to the individual.

[0077] In some aspects, the method further includes administering to an individual one or more agents that regulate the expression of one or more of the following: (a) Acaca, Ambra1, Amfr, Arih1, Cbll1, Cfap57, Cnot4, Cyld, Dcaf7, Det1, Dpf2, Eed, Efcab8, Egr2, Fasn, Fbxw7, Foxo3, Gsk3b, Hectd3, Hira, Icos, Ifnar1, Ikbke, Ints12, Junb, Kat6a, Kctd10, Kctd13, Kctd21, Kctd5, Klhl30, Klhl6, Lztr1, March6, Msl2, Nf1, Nsd1, Patz1, Pias1, Prdm1, Pten, Rfwd2, Rnf139, Socs3, Spag16, Strap, Stub1, Syk, Tab1, Tank, Tbk1, Tnf, Trim45, Trip12, Ube2j2, Wdfy2, Wdr61, Wdr81, Wdr91, Zbtb25, Zfp106, Zf p91 and Zmiz2; and / or (b) Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fus, Gm9840, Hif1a, Huwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, Ranbp2, Rbbp 6. Rbck1, Rbx1, Rc3h1, Rela, Rlim, Rnf144a, Rnf31, Rnf7, Seh1l, Skp1a, Spop, Ssr3, Tbl1xr1, Tceb1, Tceb2, Tceb3, Tdpoz5 , Thoc3, Tlr4, Traf6, Trim28, Trim33, Ube2d3, Ube2f, Ube2h, Ube2i, Ubr4, Ubr5, Vhl, Wdr20, Wdr26, Wdr33, Zbtb17 and Zbtb7b.

[0078] In another aspect, the present invention provides a kit comprising a modulator of the interaction between (a) Fbxw11 and (b) Nfkb1 or Nfkb2, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease according to any of the methods provided herein. In some aspects, the kit includes a packaging insert containing instructions for administering the modulator to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

[0079] In another aspect, the present invention provides a method for monitoring the response of an individual suffering from cancer, an inflammatory disease, or an autoimmune disease to treatment with a modulator of the interaction between (a) Fbxw11 and (b) Nfkb1 or Nfkb2, the method comprising: (i) determining the expression level of an active form of one or both of Nfkb1 and Nfkb2 in a biological sample obtained from the individual at a time point following administration of the modulator; and (ii) comparing the expression level of an active form of one or both of Nfkb1 and Nfkb2 in the biological sample with a reference level, thereby monitoring the individual's response to treatment with the modulator.

[0080] In some respects, the reference level is selected from the group consisting of: (i) the expression levels of one or two genes in a biological sample obtained from an individual prior to the administration of the regulator; (ii) the expression levels of one or two genes in a reference population; (iii) a pre-specified expression level for one or two genes; or (iv) the expression levels of one or two genes in a biological sample obtained from an individual at a previous time point, wherein the previous time point is after the administration of the regulator.

[0081] In some respects, the individual has cancer, the expression level of one or both of the active forms of Nfkb1 and Nfkb2 in a biological sample obtained from the individual is reduced relative to a reference level, and the method further includes administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that increases the expression and / or activity of Fbxw11.

[0082] In some respects, the individual suffers from an inflammatory disease or an autoimmune disease, the expression level of one or both of the active forms of Nfkb1 and Nfkb2 in a biological sample obtained from the individual is increased relative to a reference level, and the method further includes administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that reduces the expression and / or activity of Fbxw11.

[0083] On the other hand, the present invention provides a method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering to the individual an effective amount of a cell therapy comprising cells containing alterations to at least two genes from one or more of the following cofunctional gene modules: (a) module M1, which includes Aamp, Bop1, Cirh1a, Dcaf13, Grb2, Myc, Nle1, Nol10, Pak1ip1, Ptpn11, Rack1, Raf1, Rrp9, Taf5, Tbl3, Uhrf1, ... Utp15, Utp18, Vprbp, Wdr3, Wdr36, Wdr43, Wdr5, Wdr74 and Wdr75; (b) Module M2, which includes Ago2, Ahr, Anapc13, Bach1, Baz1a, Bid, Bptf, Brca1, Brwd3, Btbd1, Cblc, Ccnf, Cdc27, Cntn4, Copa, Copb2, Coro1a, Cpne9, Cul4b, Ddb1, Dido1, E4f1, Ecel1, Fbxl14, Fbxl5, Fb xo11, Fbxo42, Fzr1, Gemin5, Gm10697, Gm9117, Gtf2h2, Gtf3c1, Hdac4, Hectd1, Ift122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23, Klhl3, Kmt2b, LOC100861784, Lrr1, Lrrc41, Map3k7, Mdm4, Mib1, Mkrn1, Mnat1, Naca, Nsmaf, Ogt, Pa2g4, Pcif 1. Ppp1r11, Prc1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah2, Taf3, Tdpoz2, Tmem183a, Tnfsf11, Tradd, Traf3ip2, Trim35, Trim7, Tssc1, Ttc3, Ube2n, Ufl1, Unkl, Upf1, Vdr, Wdhd1, Wdr48, Wdr95, Wwp1, Ybx1, Zbtb14, Zbtb49, Zbtb7a and Zmiz1;(c) Module M3, which includes Akt1, Ankfy1, Apc, Arcc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbxl13, Fbxo28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, Mlst8, Mtor, Nosip, Paf1, Pi k3r4, Pparg, Ppp2r2a, Ppp2r2d, Preb, Rbbp4, Rbbp5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13, Sec31a, Smad2, Syvn1, Taf5l, Traf2, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1, and Zbtb11; (d) Module M4, which includes Cdc 40, Ddx41, Plrg1, Ppil2, Ppwd1, Prpf19, Prpf4, Sart1, Smu1, Snrnp40 and Wdr70; (e) Module M5, which includes Acaca, Ambra1, Amfr, Arih1, Cbll1, Cfap57, Cnot4, Cyld, Dcaf7, Det1, Dpf2, Eed, Efcab8, Egr2, Fasn, Fbxw7, Foxo3, Gsk3b, Hectd3, Hira, Icos, Ifnar1, Ikbke, Ints12, Junb, Kat6a, Kctd10, Kctd13, Kctd21, Kctd5, Klhl30, Klhl6, Lztr1, March6, Msl2, Nf1, Nfkb1, Nsd1, Patz1, Pias1, Prdm1, Pten, Rfwd2, Rnf139, Socs3 , Spag16, Strap, Stub1, Syk, Tab1, Tank, Tbk1, Tnf, Trim45, Trip12, Ube2j2, Wdfy2, Wdr61, Wdr81, Wdr91, Zbtb25, Zfp106, Zfp91 and Zmiz2;And (f) module M6, which includes Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fbxw11, Fus, Gm9840, Hif1a, Huwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, Ranbp2, Rb bp6, Rbck1, Rbx1, Rc3h1, Rela, Rlim, Rnf144a, Rnf31, Rnf7, Seh1l, Skp1a, Spop, Ssr3, Tbl1xr1, Tceb1, Tceb2, Tceb3, Tdpoz 5. Thoc3, Tlr4, Traf6, Trim28, Trim33, Ube2d3, Ube2f, Ube2h, Ube2i, Ubr4, Ubr5, Vhl, Wdr20, Wdr26, Wdr33, Zbtb17 and Zbtb7b. ;

[0084] On the other hand, the present invention provides a method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering to the individual an effective amount of a cell therapy comprising cells containing alterations to at least two genes from one or more of the following gene sets: (a) gene set 1, comprising Aamp, Actb, Alcam, Ambra1, Anxa2, Aprt, Atp5e, B2m, Btf3, Ccdc88a, Cdh1, Chd4, Cirh1a, Cox4i1, Cox7a2l, Crebbp, Ctsb, Dcaf13, Ddx41, Eef1a1, Eef1b2, Eef1g , Eef2, Eif1, Eif3e, Eif3f, Eif3i, Eif3k, Fau, Gapdh, H2-D1, H2-K1, H2-M2, Hsp90ab1, Hspa5, Hspa8, Il1rn, Laptm5, Lhfpl2, March6, Ms4a7, Mtor, M yc, Naca, Ncl, Nf1, Nol10, Npm1, Ogt, Pabpc1, Paf1, Plrg1, Pparg, Psap, Rack1, Raf1, Rheb, Rpl10, Rpl10a, Rpl11, Rpl12, Rpl13, Rpl13a, Rpl14, Rpl 15. Rpl17, Rpl18, Rpl18a, Rpl19, Rpl21, Rpl22, Rpl22l1, Rpl23, Rpl23a, Rpl24, Rpl26, Rpl27a, Rpl28, Rpl29, Rpl3, Rpl30, Rpl31, Rpl32, Rpl34, R pl35, Rpl35a, Rpl36, Rpl36a, Rpl37, Rpl37a, Rpl38, Rpl39, Rpl4, Rpl41, Rpl5, Rpl6, Rpl7, Rpl7a, Rpl8, Rpl9, Rplp0, Rplp1, Rplp2, Rps10, Rps11, R ps12, Rps13, Rps14, Rps15, Rps15a, Rps16, Rps17, Rps18, Rps19, Rps2, Rps20, Rps21, Rps23, Rps24, Rps25, Rps26, Rps27, Rps27a, Rps28, Rps29, Rps 3. Rps3a1, Rps4x, Rps5, Rps6, Rps7, Rps8, Rps9, Rpsa, Rptor, Sgk1, Ssr4, Tab1, Taf5, Tpt1, Uhrf1, Uqcrh, Utp15, Wdr3, Wdr36, Wdr43, Wdr5 and Zbtb25;(b) Gene set 2, which includes AI314180, Abcc1, Acod1, Akr1a1, Alas1, Alox5ap, Ampd3, Arih1, Ass1, B430306N03Rik, Bach1, Blvrb, Bmi1, Brca1, Btbd1, Btg1, Cat, Ccr5, Cd36, Cd52, Cd53, Cd81, Chd4, Chpf2, Clec4n, Crebbp, Creg1, Cul3, Cx cl3, Cyb5a, Dap, Dars, Dck, Ddb1, Ddit3, Egr2, Eif3f, Eif3i, Ep300, Esd, Fbxl5, Fbxw11, Gbe1, Gclm, Gdap10, G m9840, Gss, Gstm1, H3f3b, Hmox1, Hvcn1, Il1f9, Inhba, Keap1, Lipa, Lmo4, Map3k7, Mcl1, Mcoln2, Met, Mgst2, Mm p12, Mmp19, Mmp8, Mylip, Nampt, Nedd8, Nf1, Npy, Nrp1, Nup43, Nupr1, Paf1, Pf4, Pgd, Phlda1, Pla2g7, Plet1, P pfibp2, Prdx1, Prdx6, Preb, Prkcb, Procr, Ptgr1, Ptpn1, Raf1, Rbx1, Rhob, Rnasel, Rnf128, Runx2, Sdc4, Sec13 , Seh1l, Skp1a, Slc43a2, Slc48a1, Slc7a11, Slpi, Smad2, Srxn1, Taldo1, Tarm1, Thbs1, Tlr2, Tlr4, Tma16, Tpm 4. Traf2, Traf5, Traf6, Trip12, Tubb2a, Txnrd1, Ube2d3, Ube2n, Ubr5, Uchl1, Upf1, Wdr43, Wdr61, Zbtb17 and Zyx;(c) Gene set 3, which includes Acp5, Ankfy1, Arpc1b, Atp6v0d2, Bptf, Brap, C5ar1, Ccdc88a, Cd14, Cd36, Cd63, Cebpb, Chd4, Clec4d, Clec5a, Cpd, Creg1, Ctsb, Ctsz, Cul3, Ddhd1, Dnmt3a, Egr2, Emb, and F6300. 28O10Rik, Fabp5, Fam46c, Fbxo42, Fcgr2b, Fn1, Foxo3, Fpr1, Ftl1, Gadd45a, Glrx, Gpnmb, Gp r84, Huwe1, Icam1, Id1, Il1f9, Kctd10, Keap1, Klhl6, Lcn2, Lgals1, Lgals3, Lgmn, Lipa, Lpca t2, Ly6c2, March6, Metrnl, Mgll, Mt1, Mtor, Myof, Naaa, Naca, Nf1, Paf1, Phlda1, Pid1, Pik3 r4, Pld3, Plet1, Plk2, Pou2f2, Pparg, Prdx5, Psap, Ptpn11, Rab3il1, Rela, Rfwd2, Rnase2a, S 100a1, S100a11, S100a8, Saa3, Sdc3, Serpinb2, Slamf7, Snx18, Sod2, Spata13, Stap1, Strap, Tab1, Tceb2, Tgfbi, Thbs1, Trem1, Upf1, Upp1, Vat1, Wdfy3, Wfdc21, 2010005H15Rik and Zbtb25;(d) Gene set 4, which includes AC160336.1, Actb, Actg1, Ankfy1, Arhgdib, Bptf, Brap, Bri3, Ccr2, Ccr5, Cd274, Cdkn1a, Cfl1, Chd4, Clec4a2, Copa, Coro1a, Cotl1, Crip1, Cul1, Cul3, Dars, Ddhd1, Ddit3, Ear2, Eif3f, Eif3i, Ep300, Fbxw11, Flna, Gbp2, Gbp5, Grb2, Gtf3c1, H2-D1, H2-K1, Huwe1, If i27l2a, Il1rn, Keap1, Klk1b1, Lcp1, Lgals1, Lpl, Lrr1, Lsp1, Malat1, Marcksl1, Med8, Mgll, Mndal, Mtor, Naca, Nedd8, Nf1, Paf1, Pfn1, Pi k3r4, Pten, Ptma, Ptpn11, Rack1, Rela, Rnf20, Sdc4, Skp1a, Taf3, Taf5, Tlr4, Tmsb4x, Ubb, Ube2i, Upf1, Vhl, Wdfy3, Wdr43, Wdr82 and Wfdc17;(e) Gene set 5, which includes AA467197, AW112010, Abcg1, Acod1, Bcl2a1b, Bcl2a1d, Cav1, Ccl17, Ccl3, Ccl4, Cd14, Cd200r1, Cd300lf, Cdkn1a, Cebpb, Cflar, Chd4, Clec4e, Clic4, Copa, Cpd, Cpeb4, Cul1, Cul3, Cx cl1, Cxcl2, Cxcl3, Ehd1, Ep300, Fam102b, Fam20c, Fbxw11, Gda, Gpr84, Hist1h1c, Hivep3, Ikbke, I kbkg, Il12b, Il1a, Il1b, Il6, Ing3, Inhba, Kctd21, Klf4, Laptm5, Mafb, Malat1, Malt1, Marcks, Ma rcksl1, Marco, Met, Mtpn, Nabp1, Nedd8, Nfkb1, Nfkbiz, Nlrp3, Nrp2, Nup62, Ogt, Paf1, Plek, Plrg 1. Ppfia3, Prpf19, Ptgs2, Ptx3, Rassf4, Rbx1, Rela, Rfwd2, Rnf31, Serpinb2, Sh3bp5, Skp1a, Slc7 a11, Slc7a2, Slco3a1, Slfn2, Smad2, Smu1, Socs6, Sod2, Spop, Stub1, Tank, Tbk1, Tceb3, Tlr4, Tnf , Tnfaip3, Tnfsf15, Tradd, Traf6, Trip12, Txnip, Ube2d3, Ube2i, Ube2n, Wdr82, Zbtb17 and Zc3h12c;(f) Gene set 6, which includes AA467197, Ahr, Akt1, Ankfy1, Axl, Bhlhe40, Bhlhe41, Btg1, Ccl17, Ccl22, Ccr2, Cd40, Cd52, Cd74, Cebpb, Chd4, Clec4e, Clec4n, Clic4, Cst3, Cstf1, Ctsb, Ctsd, Cxcl16, Dcstamp, Egr2, Etv3, Fabp4, Fabp5, Fam20c, Fbxw7, Fbxw9, Foxo3, Fpr1, Fth1, Ftl1, Gbp2, Gbp5, Gm2a, Gnb1, Gnb2, G rb2, Grk3, Gsk3b, H2-Aa, H2-Ab1, Hmox1, Igf1, Il4i1, Irf4, Itgax, Jak2, Jund, Kcmf1, Klhl6, Kmt2d, Lgals1, Lyz2, March6, Mgl2, Mmp12, Mtor, Myc, N dufa4, Nectin2, Nf1, Nfkb1, Pfkp, Pid1, Pik3r4, Plet1, Pmp22, Pten, Ptpn1, Ptpn11, Rheb, Rilpl2, Rptor, S100a8, Sart1, Scimp, Sdcbp, Sema4a, Sgk1 Slamf9, Smad2, Srgn, Stat5a, Tab1, Taf5l, Tank, Tceb1, Tceb2, Tlr2, Tlr4, Traf2, Traf3, Ube2n, Vcan, Wdfy3, Wdr26, Wdr61, and Zfp36l1; (g) Gene set 7, which includes Abca1, Actb, Ambra1, Atf4, Atp5g1, Atp5j, Atp5j2, Bcl2a1b, Calm1, Cfl1, Chd4, Copa, Copb2, Cotl1, Cox8a, Cul3, Cybb, Dbi, Ddit3, Eef1a1, Eif3f, E if3i, Fbxo28, Fcer1g, Gpx1, Grb2, H2-M2, H2afz, H3f3a, Il1rn, Inhba, Keap1, Kmt2d, Lhfpl2, Ly6e, March6, Med8, Mtor, Nedd8, Nf1, Nme1, Ogt, Paf1, Plrg1, Pnp, Pparg, Rack1, S100a10, S100a4, S100a6, Sdc4, Sec13, Serf2, Sgk1, Smad2, Smu1, Sqstm1, Tab1, Taf3, Trp53, Uhrf1, Wdr43, Wdr61 and Zbtb25;(h) Gene set 8, which includes Aamp, Acsl1, Ambra1, Arf4, Arih2, Atf4, Bop1, C1qb, Calr, Canx, Ccng1, Cdkn1a, Chd4, Cirh1a, Clec2d, Copa, Copb2, Cope, Cpd, Ctss, Cul3, Dad1, Dap, Dcaf13, Ddit3, Ddx41, Dstn, Eif 3f, Eif3i, Erp29, Fbxw7, Fth1, Ftl1, Gm9840, Grb2, Gtf3c1, Herpud1, Hif1a, Hnrnpa3, Hsp90b1, Hs pa5, Ift20, Keap1, Kmt2d, Krtcap2, Lgals3, Lrr1, Lyz2, Manf, Map3k7, Mthfd2, Mtor, Myc, Naca, Ne dd8, Nf1, Nol10, Ostc, P4hb, Pdia3, Pdia4, Pdia6, Phgdh, Plrg1, Preb, Prpf19, Pten, Ptpn1, Rack1 , Rbx1, Rela, Rpl22l1, Rpn1, Rps19, Rrp9, Sdf2l1, Sec11c, Sec13, Sec22b, Sec31a, Sec61b, Sec61g , Selenos, Serf2, Serp1, Sf3b5, Spcs2, Ssr3, Surf4, Syvn1, Tceal9, Tceb1, Tceb2, Timm13, Tpt1, T ram1, Trp53, Ube2f, Ufm1, Uqcrq, Utp15, Vcp, Vhl, Vprbp, Wdr36, Wdr43, Wdr5, Wdr74, Wdr75 and Xbp1;(i) Gene set 9, which includes Acod1, Adam8, Atp5g3, Brap, C3ar1, Ccl2, Ccl3, Ccl4, Ccl7, Ccnd1, Cd300ld, Cd63, Ch25h, Chd4, Chil3, Crip1, Ctsb, Ctsl, Cul1, Cul3, Cxcl1, Cyp51, Det1, Ear2, Egr2, F10, Fbxo42, F bxw11, Ffar2, Fpr2, Fyb, Gas7, Gm9840, Gnb2, Gpnmb, Grb2, Gsk3b, Hmgcs1, Huwe1, Ifitm3, Il1f9, Itgam, Jun, Kctd12, Kctd5, Keap1, Klhdc4, Kmt2c, Kmt2d, Lgals1, Lgals3, Lmna, Lmo4, Lrpap1, Ly6 c2, Lztr1, Maf, March6, Mcemp1, Mmp12, Mmp13, Mmp8, Msr1, Mtor, Naaa, Naca, Nf1, Nfkbiz, Npc2, N py, Paf1, Pdpn, Pf4, Plet1, Pparg, Prkcd, Pten, Ptgs2, Ptpn1, Ptpn11, Ptprc, Ptx3, Rbbp5, Rela, R fwd2, Rheb, Rptor, S100a6, Saa3, Scap, Scd2, Serpinb2, Serpinb6a, Sgk1, Slc7a11, Smad2, Srgn, Syk, Syngr1, Timp2, Trem2, Ube2h, Ube2i, Ucp2, Vasp, Vhl, Wdr26, Wfdc21, Ybx1, Zbtb7a and Zfp36l2;(j) Gene set 10, which includes Acaca, Ak4, Aldoa, Aldoc, Anapc13, Anxa2, Arih2, Arnt, Basp1, Bnip3l, Bsg, C3ar1, Ccl9, Cd52, Chil3, Copa, Cul2, Cul3, Cul5, Egr2, Eif3i, Eif4ebp1, Emilin2, Eno1, Ep300, Fam162a, Gapdh, Gbe1, Gpi1, Gsn, Herpud1, Hif1a, Higd1a, Hilpda, Hk1, Hk2, Hmox1, Huwe1, Ier3, Kctd10, Klk1b1, Ldha, Lgals3, Lipa, Lmo4, Lpcat2, L yz2, March6, Mif, Mt1, Mt2, Mtor, Myc, Ndufv3, Nf1, Pdk1, Pfkl, Pgam1, Pgk1, Pgm2, P km, Prdx1, Prelid1, Ptpn1, Ptpn11, Rbpj, Rfwd2, Rilpl2, Rnase2a, Sacs, Scd2, Sdc3, Sdc4, Sec13, Slamf9, Slc16a3, Slc2a1, Slc7a2, Smu1, Socs3, Strap, Tarm1, Tceb1, T ceb2, Tgm2, Tlr4, Tpi1, Trf, Ube2f, Vhl, Vim, Wdr43, Wdr82, Wfdc17 and 2010005H15Rik;(k) Gene set 11, which includes AA467197, Apobec1, Apoe, C1qa, C1qb, C1qc, C3, Car4, Ccl22, Ccl3, Ccl4, Ccl6, Ccl9, Cd83, Cdc40, Cebpb, Ch25h, Chd4, Copa, Crebbp, Cul1, Ddhd1, Ddx41, Egr2, Eif3f, Eif3i, Ep300, Fam49a, Fbxw11, Fn1, Fnbp1l, Gadd45b, Hdac4, Icam1, Icosl, Id2, Ikbkg, Il1a, Il4i1, Inhba, I tgax, Itgb2, Kctd10, Klk1b11, Lpl, Maf, Marcks, Marcksl1, Med8, Met, Mmp12, Ms4a6c, Ms4a7, Mt2, Mycbp2, Naca, Nedd8, Nfkbia, Phlda1, Plaur, P lrg1, Pparg, Ppfibp2, Prpf19, Ptpn1, Rassf4, Rfwd2, Ring1, Rnase2a, Rpl12, Scimp, Sec13, Skp1a, Slc43a2, Smu1, Sqstm1, Syk, Syvn1, Taf5l, Tc eb2, Tmem176a, Tmem176b, Tnfaip2, Traf3, Ufm1, Upp1, Wdr5, Wdr70, Wdr82, Wfdc17, Wfdc21, 0610012G03Rik, Zbtb7a and Zyx; (l) gene set 12, which includes Ambra1, Aplop2, Atp5g1, Atpif1, B2m, Ccdc88a, Chd4, Copa, Cyba, Ddit3, Ear2, Egr2, Eif3f, Eif3i, Eif5, Fcgrt, Grn, H2-M2, H2-Q6, Hint1, Id1, Ifi204, It gal, Kctd12, Laptm5, Lgals3, Ly6e, Mgst1, Mpeg1, Mtdh, Nf1, Nfe2l2, Nupr1, Paf1, Pparg, Prpf19, Psmb5, Psmb6, Pycard, Rack1, Rnase4, Rpl22l1 , Rpl37a, Rplp0, Sart1, Sdc3, Sec61b, Smad2, Smdt1, Smu1, Spp1, Syvn1, Tab1, Taf5, Taf5l, Tagln2, Tmsb10, Traf2, Traf3, Trf, Trp53, Upf1 and Wdr5;(m) Gene set 13, which includes Ankfy1, Anxa1, Anxa5, Aph1c, Brap, C3ar1, Ccnd2, Ccr1, Cd300lf, Cd38, Cd68, Cd9, Cdc27, Cdc40, Cebpb, Chd4, Chst11, Clec4e, Creb5, Cul1, Cul3, Cxcl3, Cyba, Dstn, Eif3f, Eif3i, Emp1, Epha4, Fam102b, Fam46a, Fbxw11, Fn1, Foxo3, Ftl1, Furin, Gas7, Gdf15, Grb2, H2-K1, Huwe1, Icam1, Il7r, Inhba, Keap1, Klhdc4, Klk1b11, Lgal s3, Lpl, Ly6c2, Lyz2, March6, Mbnl1, Mmp14, Mmp8, Ms4a7, Naca, Neat1, Nf1, Nrp2, Pli n2, Plk2, Plrg1, Polr2l, Prdx1, Pten, Ptpn1, Rack1, Rasgef1b, Rasgrp1, Rela, Rnf20, Rnh1, Rpl22l1, Rrp9, Saa3, Scd2, Sdc4, Sec13, Selenoh, Serp1, Skp1a, Slamf7, Slc7a2 , Smu1, Spp1, Tab1, Taf5, Ube2d3, Ubr4, Upf1, Vim, Wdr43, Wdr5, Wdr70, Wdr82 and Zbtb25;(n) Compound 14, strain AC160336.1, Adgre1, Adgre4, Adgrl2, Anxa1, B2m, C1qb, C3, Car4, Ccdc8 8a, Ccl6, Cd52, Cdc40, Chd4, Chil3, Crip1, Ctsk, Ddx41, Dpf2, Egr2, Eif3i, Ep300, F7. Fcer1g, Fn1, Foxo3, Gpx3, H2-D1, H2-K1, H2-Q6, H2-Q7, H3f3b, Hira, Hsp90aa1, Hvcn1. Id2, Ifi203, Il18, Il1f9, Kdm5c, Klhl6, Lgals1, Lgals3, Ly6e, Malt1, March6, Marks Mcub, Med8, Mpc1, Ms4a6d, Msrb1, Mt1, Mt2, Nedd8, Nfe2l2, Nov, Npc2, Paf1, Pdzk1ip1 Phgdh, Pias1, Pla2g7, Plrg1, Ppic, Ppil2, Ppwd1, Prkcd, Prpf19, Ptges, Rab32, Rbx1 Rela, Rps20, S100a11, Sart1, Selenow, Smu1, St8sia4, Tab1, Taf5l, Tceb2, Tmem176a Tmem176b, Tnip3, Traf2, Tyrobp, Ube2i, Uchl1, Wdr5, Wdr70, Wdr82, Zbtb25, and Zfp106.And (o) gene set 15, which includes AC160336.1, Adgre1, Ahnak, Alcam, Aprt, Bcl2l11, Blvrb, Brap, Bub3, C1qb, C1qc, C3ar1, Cd300c2, Cd33, Cd68, Cdc40, Cebpb, Chchd2, Clec12a, Clec4n, Copa, Csf1r, Ctsz, Cul3, Cul5, Cyba, Ddx41, Dstn, Egr2, Ep300, F7, Fbxw7, Fcer1g, Fcgr2b, Gmfg, Gngt2, Gpr84, Hsp90aa1, Huwe1, Igf1, Kat6a, Kctd12b, Kdm5c, Keap1, Kmt2d, L st1, Mmp14, Mpeg1, Myc, Naca, P2ry14, Paf1, Pirb, Plrg1, Pou2f2, Pparg, Ppil2, Ppwd 1. Prkcd, Prpf19, Prpf4, Ptpn1, Ptpn18, Rack1, Rbbp5, Rnf20, Rnf40, Rnf7, Rps27l, Sa t1, Serpinb2, Smu1, Socs3, Spp1, Taf5, Tank, Tceb1, Tceb2, Tgm2, Tnfsf15, Traf2, Tre m2, Tyrobp, Ufm1, Vcan, Wdr1, Wdr33, Wdr43, Wdr5, Wdr61, Wdr70, Wdr82, Wfdc21 and Ybx1. ;

[0085] In some respects, this cell therapy is dendritic cell therapy, macrophage therapy, adoptive T-cell therapy (ACT), tumor-infiltrating lymphocyte (TIL) therapy, engineered T-cell receptor (TCR) therapy, chimeric antigen receptor T-cell (CAR-T) therapy, CAR-Treg therapy, or natural killer (NK) cell therapy.

[0086] In another aspect, the present invention provides a kit comprising a cell therapy comprising cells containing alterations to at least two genes of one or more of the cofunctional gene modules provided above, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease according to the methods provided herein.

[0087] In another aspect, the present invention provides a kit comprising reagents for modifying cells to include alterations to at least two genes in one or more of the cofunctional gene modules provided above, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease according to the methods provided herein.

[0088] In some respects, the kit includes a packaging insert containing instructions for administering the medication to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0089] In another aspect, the present invention provides a kit comprising a cell therapy comprising cells containing alterations to at least two genes from one or more of the gene sets provided above, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease according to the methods provided herein.

[0090] In another aspect, the present invention provides a kit comprising reagents for modifying cells to include alterations to at least two genes from one or more of the gene sets provided above, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease according to the methods provided herein.

[0091] In some respects, the kit includes a packaging insert containing instructions for administering the medication to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0092] On the other hand, the present invention provides a genetically modified isolated cell comprising alterations to at least two genes in one or more of the following cofunctional gene modules: (a) module M1, comprising Aamp, Bop1, Cirh1a, Dcaf13, Grb2, Myc, Nle1, Nol10, Pak1ip1, Ptpn11, Rack1, Raf1, Rrp9, Taf5, Tbl3, Uhrf1, Utp15, Utp18, Vprbp, Wdr3, Wdr36, Wdr4 3. Wdr5, Wdr74 and Wdr75; (b) Module M2, which includes Ago2, Ahr, Anapc13, Bach1, Baz1a, Bid, Bptf, Brca1, Brwd3, Btbd1, Cblc, Ccnf, Cdc27, Cntn4, Copa, Copb2, Coro1a, Cpne9, Cul4b, Ddb1, Dido1, E4f1, Ecel1, Fbxl14, Fbxl5, Fbxo11, Fbxo42, Fzr1, Gemin 5. Gm10697, Gm9117, Gtf2h2, Gtf3c1, Hdac4, Hectd1, Ift122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23, Klhl 3. Kmt2b, LOC100861784, Lrr1, Lrrc41, Map3k7, Mdm4, Mib1, Mkrn1, Mnat1, Naca, Nsmaf, Ogt, Pa2g4, Pcif1, Ppp1r11, P rc1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah2, Taf3, Tdpoz2, Tmem183a, Tnfsf11, Tradd, Traf3ip2, Trim3 5. Trim7, Tssc1, Ttc3, Ube2n, Ufl1, Unkl, Upf1, Vdr, Wdhd1, Wdr48, Wdr95, Wwp1, Ybx1, Zbtb14, Zbtb49, Zbtb7a and Zmiz1;(c) Module M3, which includes Akt1, Ankfy1, Apc, Arcc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbxl13, Fbxo28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, Mlst8, Mtor, Nosip, Paf1, Pi k3r4, Pparg, Ppp2r2a, Ppp2r2d, Preb, Rbbp4, Rbbp5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13, Sec31a, Smad2, Syvn1, Taf5l, Traf2, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1, and Zbtb11; (d) Module M4, which includes Cdc 40, Ddx41, Plrg1, Ppil2, Ppwd1, Prpf19, Prpf4, Sart1, Smu1, Snrnp40 and Wdr70; (e) Module M5, which includes Acaca, Ambra1, Amfr, Arih1, Cbll1, Cfap57, Cnot4, Cyld, Dcaf7, Det1, Dpf2, Eed, Efcab8, Egr2, Fasn, Fbxw7, Foxo3, Gsk3b, Hectd3, Hira, Icos, Ifnar1, Ikbke, Ints12, Junb, Kat6a, Kctd10, Kctd13, Kctd21, Kctd5, Klhl30, Klhl6, Lztr1, March6, Msl2, Nf1, Nfkb1, Nsd1, Patz1, Pias1, Prdm1, Pten, Rfwd2, Rnf139, Socs3 , Spag16, Strap, Stub1, Syk, Tab1, Tank, Tbk1, Tnf, Trim45, Trip12, Ube2j2, Wdfy2, Wdr61, Wdr81, Wdr91, Zbtb25, Zfp106, Zfp91 and Zmiz2;And (f) module M6, which includes Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fbxw11, Fus, Gm9840, Hif1a, Huwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, Ranbp2, Rb bp6, Rbck1, Rbx1, Rc3h1, Rela, Rlim, Rnf144a, Rnf31, Rnf7, Seh1l, Skp1a, Spop, Ssr3, Tbl1xr1, Tceb1, Tceb2, Tceb3, Tdpoz 5. Thoc3, Tlr4, Traf6, Trim28, Trim33, Ube2d3, Ube2f, Ube2h, Ube2i, Ubr4, Ubr5, Vhl, Wdr20, Wdr26, Wdr33, Zbtb17 and Zbtb7b. ;

[0093] On the other hand, the present invention provides a genetically modified isolated cell comprising alterations to at least two genes from one or more of the following gene sets: (a) Gene set 1, comprising Aamp, Actb, Alcam, Ambra1, Anxa2, Aprt, Atp5e, B2m, Btf3, Ccdc88a, Cdh1, Chd4, Cirh1a, Cox4i1, Cox7a2l, Crebbp, Ctsb, Dcaf13, Ddx41, Eef1a1, Eef1b2, Eef1g, Eef2, Eif1, Eif3e, Eif3f, Eif3i, Eif3 k, Fau, Gapdh, H2-D1, H2-K1, H2-M2, Hsp90ab1, Hspa5, Hspa8, Il1rn, Laptm5, Lhfpl2, March6, Ms4a7, Mtor, Myc, Naca, Ncl, Nf1, Nol10, Npm1, Ogt, Pabpc1, Paf1, Plrg1, Pparg, Psap, Rack1, Raf1, Rheb, Rpl10, Rpl10a, Rpl11, Rpl12, Rpl13, Rpl13a, Rpl14, Rpl15, Rpl17, Rpl18, Rpl18a, Rpl19, Rpl21, Rpl22, Rpl22l1, Rpl23, Rpl23a, Rpl24, Rpl26, Rpl27a, Rpl28, Rpl29, Rpl3, Rpl30, Rpl31, Rpl32, Rpl34, Rpl35, Rpl35a, Rpl36 , Rpl36a, Rpl37, Rpl37a, Rpl38, Rpl39, Rpl4, Rpl41, Rpl5, Rpl6, Rpl7, Rpl7a, Rpl8, Rpl9, Rplp0, Rplp1, Rplp2, Rps10, Rps11, Rps12, Rps13, Rps14, Rps15, Rps15a, Rps16, Rps17, Rps18, Rps19, Rps2, Rps20, Rps21, Rps23, Rps24, Rps25, Rps26, Rps27, Rps27a, Rps28, Rps29, Rps3, Rps 3a1, Rps4x, Rps5, Rps6, Rps7, Rps8, Rps9, Rpsa, Rptor, Sgk1, Ssr4, Tab1, Taf5, Tpt1, Uhrf1, Uqcrh, Utp15, Wdr3, Wdr36, Wdr43, Wdr5 and Zbtb25;(b) Gene set 2, which includes AI314180, Abcc1, Acod1, Akr1a1, Alas1, Alox5ap, Ampd3, Arih1, Ass1, B430306N03Rik, Bach1, Blvrb, Bmi1, Brca1, Btbd1, Btg1, Cat, Ccr5, Cd36, Cd52, Cd53, Cd81, Chd4, Chpf2, Clec4n, Crebbp, Creg1, Cul3, Cx cl3, Cyb5a, Dap, Dars, Dck, Ddb1, Ddit3, Egr2, Eif3f, Eif3i, Ep300, Esd, Fbxl5, Fbxw11, Gbe1, Gclm, Gdap10, G m9840, Gss, Gstm1, H3f3b, Hmox1, Hvcn1, Il1f9, Inhba, Keap1, Lipa, Lmo4, Map3k7, Mcl1, Mcoln2, Met, Mgst2, Mm p12, Mmp19, Mmp8, Mylip, Nampt, Nedd8, Nf1, Npy, Nrp1, Nup43, Nupr1, Paf1, Pf4, Pgd, Phlda1, Pla2g7, Plet1, P pfibp2, Prdx1, Prdx6, Preb, Prkcb, Procr, Ptgr1, Ptpn1, Raf1, Rbx1, Rhob, Rnasel, Rnf128, Runx2, Sdc4, Sec13 , Seh1l, Skp1a, Slc43a2, Slc48a1, Slc7a11, Slpi, Smad2, Srxn1, Taldo1, Tarm1, Thbs1, Tlr2, Tlr4, Tma16, Tpm 4. Traf2, Traf5, Traf6, Trip12, Tubb2a, Txnrd1, Ube2d3, Ube2n, Ubr5, Uchl1, Upf1, Wdr43, Wdr61, Zbtb17 and Zyx;(c) Gene set 3, which includes Acp5, Ankfy1, Arpc1b, Atp6v0d2, Bptf, Brap, C5ar1, Ccdc88a, Cd14, Cd36, Cd63, Cebpb, Chd4, Clec4d, Clec5a, Cpd, Creg1, Ctsb, Ctsz, Cul3, Ddhd1, Dnmt3a, Egr2, Emb, and F6300. 28O10Rik, Fabp5, Fam46c, Fbxo42, Fcgr2b, Fn1, Foxo3, Fpr1, Ftl1, Gadd45a, Glrx, Gpnmb, Gp r84, Huwe1, Icam1, Id1, Il1f9, Kctd10, Keap1, Klhl6, Lcn2, Lgals1, Lgals3, Lgmn, Lipa, Lpca t2, Ly6c2, March6, Metrnl, Mgll, Mt1, Mtor, Myof, Naaa, Naca, Nf1, Paf1, Phlda1, Pid1, Pik3 r4, Pld3, Plet1, Plk2, Pou2f2, Pparg, Prdx5, Psap, Ptpn11, Rab3il1, Rela, Rfwd2, Rnase2a, S 100a1, S100a11, S100a8, Saa3, Sdc3, Serpinb2, Slamf7, Snx18, Sod2, Spata13, Stap1, Strap, Tab1, Tceb2, Tgfbi, Thbs1, Trem1, Upf1, Upp1, Vat1, Wdfy3, Wfdc21, 2010005H15Rik and Zbtb25;(d) Gene set 4, which includes AC160336.1, Actb, Actg1, Ankfy1, Arhgdib, Bptf, Brap, Bri3, Ccr2, Ccr5, Cd274, Cdkn1a, Cfl1, Chd4, Clec4a2, Copa, Coro1a, Cotl1, Crip1, Cul1, Cul3, Dars, Ddhd1, Ddit3, Ear2, Eif3f, Eif3i, Ep300, Fbxw11, Flna, Gbp2, Gbp5, Grb2, Gtf3c1, H2-D1, H2-K1, Huwe1, If i27l2a, Il1rn, Keap1, Klk1b1, Lcp1, Lgals1, Lpl, Lrr1, Lsp1, Malat1, Marcksl1, Med8, Mgll, Mndal, Mtor, Naca, Nedd8, Nf1, Paf1, Pfn1, Pi k3r4, Pten, Ptma, Ptpn11, Rack1, Rela, Rnf20, Sdc4, Skp1a, Taf3, Taf5, Tlr4, Tmsb4x, Ubb, Ube2i, Upf1, Vhl, Wdfy3, Wdr43, Wdr82 and Wfdc17;(e) Gene set 5, which includes AA467197, AW112010, Abcg1, Acod1, Bcl2a1b, Bcl2a1d, Cav1, Ccl17, Ccl3, Ccl4, Cd14, Cd200r1, Cd300lf, Cdkn1a, Cebpb, Cflar, Chd4, Clec4e, Clic4, Copa, Cpd, Cpeb4, Cul1, Cul3, Cx cl1, Cxcl2, Cxcl3, Ehd1, Ep300, Fam102b, Fam20c, Fbxw11, Gda, Gpr84, Hist1h1c, Hivep3, Ikbke, I kbkg, Il12b, Il1a, Il1b, Il6, Ing3, Inhba, Kctd21, Klf4, Laptm5, Mafb, Malat1, Malt1, Marcks, Ma rcksl1, Marco, Met, Mtpn, Nabp1, Nedd8, Nfkb1, Nfkbiz, Nlrp3, Nrp2, Nup62, Ogt, Paf1, Plek, Plrg 1. Ppfia3, Prpf19, Ptgs2, Ptx3, Rassf4, Rbx1, Rela, Rfwd2, Rnf31, Serpinb2, Sh3bp5, Skp1a, Slc7 a11, Slc7a2, Slco3a1, Slfn2, Smad2, Smu1, Socs6, Sod2, Spop, Stub1, Tank, Tbk1, Tceb3, Tlr4, Tnf , Tnfaip3, Tnfsf15, Tradd, Traf6, Trip12, Txnip, Ube2d3, Ube2i, Ube2n, Wdr82, Zbtb17 and Zc3h12c;(f) Gene set 6, which includes AA467197, Ahr, Akt1, Ankfy1, Axl, Bhlhe40, Bhlhe41, Btg1, Ccl17, Ccl22, Ccr2, Cd40, Cd52, Cd74, Cebpb, Chd4, Clec4e, Clec4n, Clic4, Cst3, Cstf1, Ctsb, Ctsd, Cxcl16, Dcstamp, Egr2, Etv3, Fabp4, Fabp5, Fam20c, Fbxw7, Fbxw9, Foxo3, Fpr1, Fth1, Ftl1, Gbp2, Gbp5, Gm2a, Gnb1, Gnb2, G rb2, Grk3, Gsk3b, H2-Aa, H2-Ab1, Hmox1, Igf1, Il4i1, Irf4, Itgax, Jak2, Jund, Kcmf1, Klhl6, Kmt2d, Lgals1, Lyz2, March6, Mgl2, Mmp12, Mtor, Myc, N dufa4, Nectin2, Nf1, Nfkb1, Pfkp, Pid1, Pik3r4, Plet1, Pmp22, Pten, Ptpn1, Ptpn11, Rheb, Rilpl2, Rptor, S100a8, Sart1, Scimp, Sdcbp, Sema4a, Sgk1 Slamf9, Smad2, Srgn, Stat5a, Tab1, Taf5l, Tank, Tceb1, Tceb2, Tlr2, Tlr4, Traf2, Traf3, Ube2n, Vcan, Wdfy3, Wdr26, Wdr61, and Zfp36l1; (g) Gene set 7, which includes Abca1, Actb, Ambra1, Atf4, Atp5g1, Atp5j, Atp5j2, Bcl2a1b, Calm1, Cfl1, Chd4, Copa, Copb2, Cotl1, Cox8a, Cul3, Cybb, Dbi, Ddit3, Eef1a1, Eif3f, E if3i, Fbxo28, Fcer1g, Gpx1, Grb2, H2-M2, H2afz, H3f3a, Il1rn, Inhba, Keap1, Kmt2d, Lhfpl2, Ly6e, March6, Med8, Mtor, Nedd8, Nf1, Nme1, Ogt, Paf1, Plrg1, Pnp, Pparg, Rack1, S100a10, S100a4, S100a6, Sdc4, Sec13, Serf2, Sgk1, Smad2, Smu1, Sqstm1, Tab1, Taf3, Trp53, Uhrf1, Wdr43, Wdr61 and Zbtb25;(h) Gene set 8, which includes Aamp, Acsl1, Ambra1, Arf4, Arih2, Atf4, Bop1, C1qb, Calr, Canx, Ccng1, Cdkn1a, Chd4, Cirh1a, Clec2d, Copa, Copb2, Cope, Cpd, Ctss, Cul3, Dad1, Dap, Dcaf13, Ddit3, Ddx41, Dstn, Eif 3f, Eif3i, Erp29, Fbxw7, Fth1, Ftl1, Gm9840, Grb2, Gtf3c1, Herpud1, Hif1a, Hnrnpa3, Hsp90b1, Hs pa5, Ift20, Keap1, Kmt2d, Krtcap2, Lgals3, Lrr1, Lyz2, Manf, Map3k7, Mthfd2, Mtor, Myc, Naca, Ne dd8, Nf1, Nol10, Ostc, P4hb, Pdia3, Pdia4, Pdia6, Phgdh, Plrg1, Preb, Prpf19, Pten, Ptpn1, Rack1 , Rbx1, Rela, Rpl22l1, Rpn1, Rps19, Rrp9, Sdf2l1, Sec11c, Sec13, Sec22b, Sec31a, Sec61b, Sec61g , Selenos, Serf2, Serp1, Sf3b5, Spcs2, Ssr3, Surf4, Syvn1, Tceal9, Tceb1, Tceb2, Timm13, Tpt1, T ram1, Trp53, Ube2f, Ufm1, Uqcrq, Utp15, Vcp, Vhl, Vprbp, Wdr36, Wdr43, Wdr5, Wdr74, Wdr75 and Xbp1;(i) Gene set 9, which includes Acod1, Adam8, Atp5g3, Brap, C3ar1, Ccl2, Ccl3, Ccl4, Ccl7, Ccnd1, Cd300ld, Cd63, Ch25h, Chd4, Chil3, Crip1, Ctsb, Ctsl, Cul1, Cul3, Cxcl1, Cyp51, Det1, Ear2, Egr2, F10, Fbxo42, F bxw11, Ffar2, Fpr2, Fyb, Gas7, Gm9840, Gnb2, Gpnmb, Grb2, Gsk3b, Hmgcs1, Huwe1, Ifitm3, Il1f9, Itgam, Jun, Kctd12, Kctd5, Keap1, Klhdc4, Kmt2c, Kmt2d, Lgals1, Lgals3, Lmna, Lmo4, Lrpap1, Ly6 c2, Lztr1, Maf, March6, Mcemp1, Mmp12, Mmp13, Mmp8, Msr1, Mtor, Naaa, Naca, Nf1, Nfkbiz, Npc2, N py, Paf1, Pdpn, Pf4, Plet1, Pparg, Prkcd, Pten, Ptgs2, Ptpn1, Ptpn11, Ptprc, Ptx3, Rbbp5, Rela, R fwd2, Rheb, Rptor, S100a6, Saa3, Scap, Scd2, Serpinb2, Serpinb6a, Sgk1, Slc7a11, Smad2, Srgn, Syk, Syngr1, Timp2, Trem2, Ube2h, Ube2i, Ucp2, Vasp, Vhl, Wdr26, Wfdc21, Ybx1, Zbtb7a and Zfp36l2;(j) Gene set 10, which includes Acaca, Ak4, Aldoa, Aldoc, Anapc13, Anxa2, Arih2, Arnt, Basp1, Bnip3l, Bsg, C3ar1, Ccl9, Cd52, Chil3, Copa, Cul2, Cul3, Cul5, Egr2, Eif3i, Eif4ebp1, Emilin2, Eno1, Ep300, Fam162a, Gapdh, Gbe1, Gpi1, Gsn, Herpud1, Hif1a, Higd1a, Hilpda, Hk1, Hk2, Hmox1, Huwe1, Ier3, Kctd10, Klk1b1, Ldha, Lgals3, Lipa, Lmo4, Lpcat2, L yz2, March6, Mif, Mt1, Mt2, Mtor, Myc, Ndufv3, Nf1, Pdk1, Pfkl, Pgam1, Pgk1, Pgm2, P km, Prdx1, Prelid1, Ptpn1, Ptpn11, Rbpj, Rfwd2, Rilpl2, Rnase2a, Sacs, Scd2, Sdc3, Sdc4, Sec13, Slamf9, Slc16a3, Slc2a1, Slc7a2, Smu1, Socs3, Strap, Tarm1, Tceb1, T ceb2, Tgm2, Tlr4, Tpi1, Trf, Ube2f, Vhl, Vim, Wdr43, Wdr82, Wfdc17 and 2010005H15Rik;(k) Gene set 11, which includes AA467197, Apobec1, Apoe, C1qa, C1qb, C1qc, C3, Car4, Ccl22, Ccl3, Ccl4, Ccl6, Ccl9, Cd83, Cdc40, Cebpb, Ch25h, Chd4, Copa, Crebbp, Cul1, Ddhd1, Ddx41, Egr2, Eif3f, Eif3i, Ep300, Fam49a, Fbxw11, Fn1, Fnbp1l, Gadd45b, Hdac4, Icam1, Icosl, Id2, Ikbkg, Il1a, Il4i1, Inhba, I tgax, Itgb2, Kctd10, Klk1b11, Lpl, Maf, Marcks, Marcksl1, Med8, Met, Mmp12, Ms4a6c, Ms4a7, Mt2, Mycbp2, Naca, Nedd8, Nfkbia, Phlda1, Plaur, P lrg1, Pparg, Ppfibp2, Prpf19, Ptpn1, Rassf4, Rfwd2, Ring1, Rnase2a, Rpl12, Scimp, Sec13, Skp1a, Slc43a2, Smu1, Sqstm1, Syk, Syvn1, Taf5l, Tc eb2, Tmem176a, Tmem176b, Tnfaip2, Traf3, Ufm1, Upp1, Wdr5, Wdr70, Wdr82, Wfdc17, Wfdc21, 0610012G03Rik, Zbtb7a and Zyx; (l) gene set 12, which includes Ambra1, Aplop2, Atp5g1, Atpif1, B2m, Ccdc88a, Chd4, Copa, Cyba, Ddit3, Ear2, Egr2, Eif3f, Eif3i, Eif5, Fcgrt, Grn, H2-M2, H2-Q6, Hint1, Id1, Ifi204, It gal, Kctd12, Laptm5, Lgals3, Ly6e, Mgst1, Mpeg1, Mtdh, Nf1, Nfe2l2, Nupr1, Paf1, Pparg, Prpf19, Psmb5, Psmb6, Pycard, Rack1, Rnase4, Rpl22l1 , Rpl37a, Rplp0, Sart1, Sdc3, Sec61b, Smad2, Smdt1, Smu1, Spp1, Syvn1, Tab1, Taf5, Taf5l, Tagln2, Tmsb10, Traf2, Traf3, Trf, Trp53, Upf1 and Wdr5;(m) Gene set 13, which includes Ankfy1, Anxa1, Anxa5, Aph1c, Brap, C3ar1, Ccnd2, Ccr1, Cd300lf, Cd38, Cd68, Cd9, Cdc27, Cdc40, Cebpb, Chd4, Chst11, Clec4e, Creb5, Cul1, Cul3, Cxcl3, Cyba, Dstn, Eif3f, Eif3i, Emp1, Epha4, Fam102b, Fam46a, Fbxw11, Fn1, Foxo3, Ftl1, Furin, Gas7, Gdf15, Grb2, H2-K1, Huwe1, Icam1, Il7r, Inhba, Keap1, Klhdc4, Klk1b11, Lgal s3, Lpl, Ly6c2, Lyz2, March6, Mbnl1, Mmp14, Mmp8, Ms4a7, Naca, Neat1, Nf1, Nrp2, Pli n2, Plk2, Plrg1, Polr2l, Prdx1, Pten, Ptpn1, Rack1, Rasgef1b, Rasgrp1, Rela, Rnf20, Rnh1, Rpl22l1, Rrp9, Saa3, Scd2, Sdc4, Sec13, Selenoh, Serp1, Skp1a, Slamf7, Slc7a2 , Smu1, Spp1, Tab1, Taf5, Ube2d3, Ubr4, Upf1, Vim, Wdr43, Wdr5, Wdr70, Wdr82 and Zbtb25;(n) Compound 14, strain AC160336.1, Adgre1, Adgre4, Adgrl2, Anxa1, B2m, C1qb, C3, Car4, Ccdc8 8a, Ccl6, Cd52, Cdc40, Chd4, Chil3, Crip1, Ctsk, Ddx41, Dpf2, Egr2, Eif3i, Ep300, F7. Fcer1g, Fn1, Foxo3, Gpx3, H2-D1, H2-K1, H2-Q6, H2-Q7, H3f3b, Hira, Hsp90aa1, Hvcn1. Id2, Ifi203, Il18, Il1f9, Kdm5c, Klhl6, Lgals1, Lgals3, Ly6e, Malt1, March6, Marks Mcub, Med8, Mpc1, Ms4a6d, Msrb1, Mt1, Mt2, Nedd8, Nfe2l2, Nov, Npc2, Paf1, Pdzk1ip1 Phgdh, Pias1, Pla2g7, Plrg1, Ppic, Ppil2, Ppwd1, Prkcd, Prpf19, Ptges, Rab32, Rbx1 Rela, Rps20, S100a11, Sart1, Selenow, Smu1, St8sia4, Tab1, Taf5l, Tceb2, Tmem176a Tmem176b, Tnip3, Traf2, Tyrobp, Ube2i, Uchl1, Wdr5, Wdr70, Wdr82, Zbtb25, and Zfp106.And (o) gene set 15, which includes AC160336.1, Adgre1, Ahnak, Alcam, Aprt, Bcl2l11, Blvrb, Brap, Bub3, C1qb, C1qc, C3ar1, Cd300c2, Cd33, Cd68, Cdc40, Cebpb, Chchd2, Clec12a, Clec4n, Copa, Csf1r, Ctsz, Cul3, Cul5, Cyba, Ddx41, Dstn, Egr2, Ep300, F7, Fbxw7, Fcer1g, Fcgr2b, Gmfg, Gngt2, Gpr84, Hsp90aa1, Huwe1, Igf1, Kat6a, Kctd12b, Kdm5c, Keap1, Kmt2d, L st1, Mmp14, Mpeg1, Myc, Naca, P2ry14, Paf1, Pirb, Plrg1, Pou2f2, Pparg, Ppil2, Ppwd 1. Prkcd, Prpf19, Prpf4, Ptpn1, Ptpn18, Rack1, Rbbp5, Rnf20, Rnf40, Rnf7, Rps27l, Sa t1, Serpinb2, Smu1, Socs3, Spp1, Taf5, Tank, Tceb1, Tceb2, Tgm2, Tnfsf15, Traf2, Tre m2, Tyrobp, Ufm1, Vcan, Wdr1, Wdr33, Wdr43, Wdr5, Wdr61, Wdr70, Wdr82, Wfdc21 and Ybx1. ;

[0094] In some respects, at least one of the changes is a loss-of-function change.

[0095] In some respects, at least one of the changes is a functional gain change.

[0096] In some respects, the genetically modified isolated cells contain loss-of-function alterations in one, two, or all three of Ldb2, Rnf165, and Traf2. In some respects, the loss-of-function alteration is a knockout (KO) mutation.

[0097] In some respects, genetically modified isolated cells contain gain-of-function alterations of CCR7. In other respects, the gain-of-function alteration is overexpression.

[0098] In another aspect, the present invention provides a method for identifying a modulator of the interaction between an F-box and a WD repeating domain 11 (Fbxw11) and a nuclear factor κB subunit 1 (Nfkb1) or a nuclear factor κB subunit 2 (Nfkb2), the method comprising: (a) providing a candidate modulator; (b) contacting Fbxw11 with Nfkb1 or Nfkb2 in the presence or absence of the candidate modulator under conditions that allow binding of Fbxw11 with Nfkb1 or Nfkb2; and (c) measuring the binding of Fbxw11 with Nfkb1 or Nfkb2, wherein an increase or decrease in binding in the presence of the candidate modulator relative to binding in the absence of the candidate modulator identifies the candidate modulator as a modulator of the interaction between Fbxw11 and Nfkb1 or Nfkb2.

[0099] In another aspect, the present invention provides a method for identifying a regulator of the downstream activity of Fbxw11, the method comprising: (a) providing a candidate regulator; (b) contacting Fbxw11 with Nfkb1 or Nfkb2 in the presence or absence of the candidate regulator under conditions that allow binding of Fbxw11 to Nfkb1 or Nfkb2; and (c) measuring the downstream activity of Fbxw11, wherein the change in downstream activity in the presence of the candidate regulator relative to the change in downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of Fbxw11.

[0100] In another aspect, the present invention provides a method for identifying a regulator of the downstream activity of Nfkb1 or Nfkb2, the method comprising: (a) providing a candidate regulator; (b) contacting Nfkb1 or Nfkb2 with Fbxw11 in the presence or absence of the candidate regulator under conditions allowing binding of Nfkb1 or Nfkb2 to Fbxw11; and (c) measuring the downstream activity of Nfkb1 or Nfkb2, wherein a change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of Nfkb1 or Nfkb2.

[0101] In some respects, the increase or decrease in binding is at least 50%, as measured by surface plasmon resonance, biolayer interference, or enzyme-linked immunosorbent assay (ELISA).

[0102] In some respects, the modulator is an inhibitor of the downstream activity of Fbxw11, Nfkb1, or Nfkb2.

[0103] In some respects, changes in downstream activity are seen as increases in the amount, intensity, or duration of downstream activity.

[0104] In some respects, changes in downstream activity are reductions in the amount, intensity, or duration of downstream activity.

[0105] In some respects, the modulator is a proteolytic targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or a repressive nucleic acid. In other respects, the repressive nucleic acid is an ASO or siRNA.

[0106] In some respects, the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bisomatic antibody, linear antibody, scFv, scFab, VH domain or VHH domain.

[0107] In some respects, the antibody or its antigen-binding fragment binds to Fbxw11.

[0108] In some respects, antibodies or their antigen-binding fragments bind to Nfkb1 or Nfkb2.

[0109] In some respects, the downstream activity is immune response activation.

[0110] In another aspect, the present invention provides a method for preventing or treating an individual’s cancer, inflammatory disease, or autoimmune disease, the method comprising administering to the individual an effective amount of a modulator identified by any of the methods provided herein, thereby treating the individual.

[0111] In another aspect, the present invention provides a method for treating cancer in an individual, the method comprising administering to the individual an effective amount of a modulator of the interaction between Fbxw11 and one or both of Nfkb1 and Nfkb2, wherein activation of the immune response is increased in the presence of the modulator.

[0112] In another aspect, the present invention provides a method for treating an individual with an inflammatory disease or an autoimmune disease, the method comprising administering to the individual an effective amount of a modulator of the interaction between Fbxw11 and one or both of Nfkb1 and Nfkb2, wherein activation of the immune response is reduced in the presence of the modulator.

[0113] On the other hand, the present invention provides a method for identifying regulators of the interaction between the ring finger and WD repeat domain 2 (Rfwd2) and a query protein selected from Forkhead Box L2 (Foxl2), JunD, WD repeat domain 82 (Wdr82); E1A-binding protein p300 (Ep300); late-promoting complex subunit 13 (Anapc13); Cullin 2 (Cul2); Cullin 5 (Cul5); E3 ubiquitin ligase 1 (Huwe1) containing HECT, UBA, and WWE domains; CREB-binding protein (Crebbp); S-phase kinase-associated protein 1 (Skp1a); developmentally downregulated gene 8 expressed by neural progenitor cells (Nedd8); Cullin 1 (Cul1); and WD repeat domain 5 (Wdr5), the method comprising: (a) providing a candidate regulator; (b) contacting Rfwd2 with a query protein in the presence or absence of the candidate regulator under conditions that allow Rfwd2 to bind to the query protein; and (c) measuring the binding of Rfwd2 to the query protein, wherein an increase or decrease in binding in the presence of the candidate regulator relative to binding in the absence of the candidate regulator identifies the candidate regulator as a regulator of the interaction between Rfwd2 and the query protein.

[0114] In another aspect, the present invention provides a method for identifying a regulator of the downstream activity of Rfwd2, the method comprising: (a) providing a candidate regulator; (b) contacting Rfwd2 with a query protein in the presence or absence of the candidate regulator under conditions allowing binding of Rfwd2 to the query protein, the query protein being selected from Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5; and (c) measuring the downstream activity of Rfwd2, wherein the change in downstream activity in the presence of the candidate regulator relative to the change in downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of Rfwd2.

[0115] In another aspect, the present invention provides a method for identifying a regulator of the downstream activity of a query protein selected from Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5, the method comprising: (a) providing a candidate regulator; (b) contacting the query protein with Rfwd2 in the presence or absence of the candidate regulator under conditions that allow the query protein to bind to Rfwd2; and (c) measuring the downstream activity of the query protein, wherein a change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of the query protein.

[0116] In some respects, the increase or decrease in binding is at least 50%, as measured by surface plasmon resonance, biolayer interference, or enzyme-linked immunosorbent assay (ELISA).

[0117] In some respects, the regulator is an inhibitor of the downstream activity of Rfwd2 or the query protein.

[0118] In some respects, changes in downstream activity are seen as increases in the amount, intensity, or duration of downstream activity.

[0119] In some respects, changes in downstream activity are reductions in the amount, intensity, or duration of downstream activity.

[0120] In some respects, the modulator is a proteolytic targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or a repressive nucleic acid. In other respects, the repressive nucleic acid is an ASO or siRNA.

[0121] In some respects, the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bisomatic antibody, linear antibody, scFv, scFab, VH domain or VHH domain.

[0122] In some respects, antibodies or their antigen-binding fragments bind to Rfwd2.

[0123] In some respects, antibodies or their antigen-binding fragments bind to the query protein.

[0124] In some respects, downstream activity involves dendritic cell or macrophage migration.

[0125] In another aspect, the present invention provides a method for preventing or treating an individual’s cancer, inflammatory disease, or autoimmune disease, the method comprising administering to the individual an effective amount of a modulator identified by the method provided herein, thereby treating the individual.

[0126] In another aspect, the present invention provides a method for treating an individual with an inflammatory disease or an autoimmune disease, the method comprising administering to the individual an effective amount of a modulator of the interaction between Rfwd2 and one or more of Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1 and Wdr5, wherein dendritic cell or macrophage migration is reduced in the presence of the modulator.

[0127] In another aspect, the present invention provides a method for treating cancer in an individual, the method comprising administering to the individual an effective amount of a modulator of the interaction between Rfwd2 and one or more of Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1 and Wdr5, wherein dendritic cell or macrophage migration is increased in the presence of the modulator.

[0128] In another aspect, the present invention provides a kit comprising a modulator of the interaction between Rfwd2 and one or more of Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5, for use in treating an individual with cancer, an inflammatory disease, or an autoimmune disease according to the methods provided herein. In some aspects, the kit includes a packaging insert containing instructions for administering the modulator to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0129] In another aspect, the present invention provides a method for identifying regulators of interactions between a protein complex and a CCAAT enhancer-binding protein (Cebp) family transcription factor, the protein complex comprising a non-receptor tyrosine protein phosphatase 11 (Ptpn11) and a ring finger and WD repeat domain 2 (Rfwd2), the method comprising: (a) providing a candidate regulator; (b) contacting the protein complex with the Cebp family transcription factor in the presence or absence of the candidate regulator under conditions allowing Rfwd2 to bind to a query protein; and (c) measuring the binding of the protein complex to the Cebp family transcription factor, wherein an increase or decrease in binding in the presence of the candidate regulator relative to binding in the absence of the candidate regulator identifies the candidate regulator as a regulator of the interaction between the protein complex and the Cebp family transcription factor.

[0130] In another aspect, the present invention provides a method for identifying a regulator of the downstream activity of a protein complex comprising Ptpn11 and Rfwd2, the method comprising: (a) providing a candidate regulator; (b) contacting the protein complex with a Cebp family transcription factor in the presence or absence of the candidate regulator under conditions allowing the protein complex to bind to the Cebp family transcription factor; and (c) measuring the downstream activity of the protein complex, wherein a change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of the protein complex.

[0131] In another aspect, the present invention provides a method for identifying regulators of downstream activity of Cebp family transcription factors, the method comprising: (a) providing a candidate regulator; (b) contacting a Cebp family transcription factor with a protein complex comprising Ptpn11 and Rfwd2 in the presence or absence of the candidate regulator under conditions allowing binding of the Cebp family transcription factor to the protein complex; and (c) measuring the downstream activity of a query protein, wherein a change in downstream activity in the presence of the candidate regulator relative to downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of the query protein.

[0132] In some respects, the increase or decrease in binding is at least 50%, as measured by surface plasmon resonance, biolayer interference, or enzyme-linked immunosorbent assay (ELISA).

[0133] In some respects, regulators are inhibitors of the downstream activity of protein complexes or Cebp family transcription factors.

[0134] In some respects, changes in downstream activity are seen as increases in the amount, intensity, or duration of downstream activity.

[0135] In some respects, changes in downstream activity are reductions in the amount, intensity, or duration of downstream activity.

[0136] In some respects, the modulator is a proteolytic targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or a repressive nucleic acid. In other respects, the repressive nucleic acid is an ASO or siRNA.

[0137] In some respects, the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bisomatic antibody, linear antibody, scFv, scFab, VH domain or VHH domain.

[0138] In some respects, antibodies or their antigen-binding fragments bind to protein complexes.

[0139] In some respects, antibodies or their antigen-binding fragments bind to Cebp family transcription factors.

[0140] In another aspect, the present invention provides a method for preventing or treating an individual’s disease or ailment related to antigen-presenting cells (APCs) and / or inflammation, the method comprising administering to the individual an effective amount of a regulator of a gene from Table 1 or Table 2, thereby treating the individual.

[0141] In some respects, regulators modulate gene expression. In other respects, regulators regulate the expression or activity of proteins encoded by genes.

[0142] In some respects, the regulators cause changes in the downstream activity of proteins encoded by the genes in Table 1 or Table 2 in the presence of the regulators relative to the downstream activity in the absence of the regulators.

[0143] In some respects, the regulators are inhibitors of the downstream activity of the genes listed in Table 1 or Table 2.

[0144] In some respects, changes in downstream activity are reductions in the amount, intensity, or duration of downstream activity.

[0145] In some respects, the regulators are activators of the downstream activity of the genes listed in Table 1 or Table 2.

[0146] In some respects, changes in downstream activity are seen as increases in the amount, intensity, or duration of downstream activity.

[0147] In some respects, the modulator is a proteolytic targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or a repressive nucleic acid. In other respects, the repressive nucleic acid is an ASO or siRNA.

[0148] In some respects, the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bisomatic antibody, linear antibody, scFv, scFab, VH domain or VHH domain.

[0149] In some respects, antibodies or their antigen-binding fragments bind to proteins encoded by genes listed in Table 1 or Table 2.

[0150] In some respects, diseases or disorders associated with APC and / or inflammation include neurodegenerative diseases, arthritis, allergies, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or blastic plasmacytoid dendritic cell tumors. In other respects, neurodegenerative diseases include MS, AD, ALS, or PD.

[0151] In some respects, APCs are dendritic cells (DCs), macrophages, or glial cells. In some respects, glial cells are microglia, astrocytes, or oligodendrocytes. In some respects, APCs are dendritic cells (DCs).

[0152] In another aspect, the present invention provides a kit comprising regulators of genes listed in Table 1 or Table 2, the kit being used to treat an individual suffering from a disease or disorder associated with APC and / or inflammation according to the methods provided herein. In some aspects, the kit includes a packaging insert containing instructions for administering the regulators to an individual suffering from a disease or disorder associated with APC and / or inflammation.

[0153] In another aspect, the present invention provides a method for monitoring the response of an individual suffering from a disease or ailment related to APC and / or inflammation to treatment with a regulator of genes listed in Table 1 or Table 2, the method comprising: (a) determining the expression level of the genes in Table 1 or Table 2 in a biological sample obtained from the individual at a time point following the administration of the regulator; and (b) comparing the expression level of the genes in Table 1 or Table 2 in the biological sample with a reference level, thereby monitoring the individual's response to treatment with the regulator. In some aspects, the reference level is selected from the group consisting of: (i) the gene expression level in a biological sample obtained from the individual prior to the administration of the regulator; (ii) the gene expression level in a reference population; (iii) a pre-specified expression level for the gene; or (iv) the gene expression level in a biological sample obtained from the individual at a previous time point, wherein the previous time point is after the administration of the regulator.

[0154] In some respects, the expression levels of genes in Table 1 or Table 2 in biological samples obtained from the individual are reduced relative to reference levels, and the method further includes administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that increases the expression and / or activity of genes in Table 1 or Table 2.

[0155] In some respects, the expression levels of genes in Table 1 or Table 2 in biological samples obtained from the individual are increased relative to reference levels, and the method further includes administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that reduces the expression and / or activity of genes in Table 1 or Table 2. Attached Figure Description

[0156] Figure 1A This is a schematic diagram illustrating the design for a large-scale Perturb-seq screening to assess the function of E3 ligases in the lipopolysaccharide (LPS) reaction in bone marrow-derived dendritic cells (BMDCs). Top row: Experimental workflow. Middle row: Perturb-Seq vector design. Bottom row: Exemplary E3 ligases and complex members known to regulate different processes.

[0157] Figure 1B This is a schematic diagram illustrating the key features of the PerturbDecode workflow. The complete workflow diagram is available at [link to full diagram]. Figure 8E As shown in the diagram. KO: knockout; PPI: protein-protein interaction; TF: transcription factor.

[0158] Figure 1C This shows the uniform manifold approximation and projection (UMAP) of the outlines of 519,535 perturbation single cells colored by cluster membership.

[0159] Figure 1DThis is a UMAP showing the outlines of 519,535 cells colored according to the characteristic score of type 2 dendritic cell (DC2)-like cells.

[0160] Figure 1E This is a UMAP showing the outlines of 519,535 cells colored according to the characteristic score of regulatory macrophage (MReg)-like cells.

[0161] Figure 1F This is a UMAP showing the outlines of 519,535 cells colored according to the characteristic score of type 1 dendritic cell (DC1)-like cells.

[0162] Figure 1G This is a UMAP showing 519,535 cell outlines stained according to cell cycle stages.

[0163] Figure 1H This is a UMAP showing the contours of 519,535 cells differentiated by macrophage and dendritic cell (DC) characteristic scores (DC maturation).

[0164] Figure 1I This is a heatmap showing the odds ratio (shaded bars) of significant (false discovery rate (FDR) < 0.15, one-sided Fisher exact test) enrichment (^) or depletion (v) of guides targeting perturbation genes (rows) in each major cell subgroup (column) in the Perturb-seq screening. Mac: Macrophages.

[0165] Figure 1J This is a pair of tables summarizing the enrichment (^) and depletion (v) of guides targeting key proteins in the major subgroup (left table) and DC2 isotype (right table), stained by E3 family type and grouped by complex. ULD: ubiquitin-like domain; DUB: deubiquitinating enzyme; NS: not significant.

[0166] Figure 2A The left side shows a pie chart (left) of the proportions of 329 significant regulators (influential perturbed genes) in each of the E3 family member types shown, and a scatter plot of UMAP embeddings showing the regulatory profiles of the 329 regulators (KO genes), colored according to their module membership. DUB: deubiquitinase; ULD: ubiquitin-like domain.

[0167] Figure 2B This is a scatter plot of UMAP embeddings showing the regulatory profiles of 1,041 affected genes, colored according to their membership in Gene Program (GP) 1-11.

[0168] Figure 2CThis is a set of regulatory matrices. Top left: Regulatory matrix (β), which shows the magnitude of the regulatory effect of each of the 329 genes (rows) perturbed (KO) on the expression of each of the 1,041 affected genes (columns). Shading indicates induction / repression in response to perturbed (KO) compared to control cells. Black horizontal and vertical lines depict co-functional modules and co-regulatory programs, respectively. Top right: Regulatory matrix showing co-functional modules. Covariance between regulatory maps in β for each of the 329 genes perturbed. Genes are clustered by module (e.g., Figure 2A Middle; shaded codes are at the top and right. Bottom: Shows the regulation matrix of the co-regulation procedure. Covariance between regulation maps in β representing the effect of each of the 1,041 genes on the expression of each gene. Genes are clustered according to a procedure (e.g., Figure 2B (The code is located at the bottom and right).

[0169] Figure 2D This is a bipartite graph showing the relationship between six co-functional modules (left) and eleven co-regulatory procedures (right). Pointed arrows: module gene activation procedures (i.e., KO repression procedures); blunt arrows: module gene repression procedures (i.e., activation procedures) (arrows are determined by significant mean differences). Key gene names are indicated.

[0170] Figure 3A This is a diagram illustrating the E3 gene regulatory network. It shows the perturbation (KO) based on the E3 ligase. Figure 2C The model shown is regulated by another E3 ligase whose expression is affected. Arrows: Expression of perturbed E3 activation targets (i.e., KO-inhibited expression). Crossed arrows: Expression of perturbed E3 repressive targets (i.e., KO-activated expression). The three E3 ligases are highly regulated "authorities" in the E3 network.

[0171] Figure 3B It is a UMAP embedding of single-cell outlines stained according to the Gaussian nuclear density of cells using control (top left), M1 (top right), or M5 (bottom) guides.

[0172] Figure 3C It is a supervised UMAP embedding of the DC2.1, DC2.2 and DC2.3 cell outlines, which uses the cell’s cofunctional module assignment as a response tag and assigns coloring (coloring code) according to the module of its guide.

[0173] Figure 3D It is a graph showing the average Wasserstein distance (bar chart) between cells with guides from different cofunctional modules (rows, columns).

[0174] Figure 3EThis is a graph (bar chart) showing the odds ratio (FDR < 0.15, one-sided Fisher exact test) of significant enrichment (^) or depletion (v) of DC subpopulations (rows) in cells with guides from each cofunctional module (column).

[0175] Figure 3F This is a graph showing the physical interactions (grey; experimental score >0, STRING Database (DB)) between each pair of 78 E3 ligases and their adaptors, or the absence of physical interactions (white), where there are at least 24 interactions (with any of the 165 E3 ligases out of 329 regulators). The full matrix is ​​in Figure 11G The diagram shows the interaction patterns. Shaded areas indicate whether the regulatory profiles of physically interacting genes have a significant (P<0.05) positive correlation, a significant (P<0.05) negative correlation, or no significant correlation. Bar chart: co-functional modules. Rows and columns are clustered hierarchically.

[0176] Figure 3G This is a graph showing the inferred activity scores (bar chart) of 32 TFs (columns) for which the target genes were significantly induced or repressed (FDR < 0.1) when each of the 41 E3 and related genes (rows) was perturbed. The full matrix is ​​in... Figure 11J As shown in the image.

[0177] Figure 3H It is a set of Venn diagrams that show the intersection between TF targets (Discriminative Regulator Expression Analysis (DoRothEA)), E3 expression targets, and gene programs.

[0178] Figure 3I It is a set of Venn diagrams that show the intersection between TF targets (DoRothEA), E3 expression targets, and gene programs.

[0179] Figure 4A This is a pair of heatmaps showing the associations of the E3 regulator with independent factors from the Independent Component Analysis (ICA). The explained variance of the effects of each of the 203 perturbation genes (left matrix columns, sum of explained variance > 25%) or the components of the CUL4-RBX1-DET1-RFWD2 complex (right matrix columns) on the effects of the 15 potential factors (rows, main plot) and all 15 factors (bottom) on 1,041 genes is shown.

[0180] Figure 4B This is a graph showing the effect size (positive or negative; bar chart) of significantly affected genes (columns; outlier load, separated by effect direction) after perturbation of each regulatory gene associated with the indicated factor (rows; outliers based on weights in the mixture matrix). Left column: co-functional modules; top column: gene program from the regulatory model.

[0181] Figure 4C Cell outlines are colored according to factor 5.1 expression scores (e.g.) Figure 1C UMAP embedding in (China).

[0182] Figure 4D Cell outlines are colored according to factor 5.2 expression scores (e.g.) Figure 1C UMAP embedding in (China).

[0183] Figure 4E This is a graph showing the effect size (positive or negative; bar chart) of significantly affected genes (columns; outlier load, separated by effect direction) after perturbation of each regulatory gene associated with the indicated factor (rows; outliers based on weights in the mixture matrix). Left column: co-functional modules; top column: gene program from the regulatory model.

[0184] Figure 4F Cell outlines are colored according to factor 6.1 expression scores (e.g.) Figure 1C UMAP embedding in (China).

[0185] Figure 4G Cell outlines are colored according to the expression score of factor 6.2 (e.g.) Figure 1C UMAP embedding in (China).

[0186] Figure 4H This is a graph showing the effect size (positive or negative; bar chart) of significantly affected genes (columns; outlier load, separated by effect direction) after perturbation of each regulatory gene associated with the indicated factor (rows; outliers based on weights in the mixture matrix). Left column: co-functional modules; top column: gene program from the regulatory model.

[0187] Figure 4I Cell outlines colored according to factor 2.1 expression scores (e.g.) Figure 1C UMAP embedding in (China).

[0188] Figure 4J Cell outlines are colored according to factor 2.2 expression scores (e.g.) Figure 1C UMAP embedding in (China).

[0189] Figure 5A It is a bar chart showing the number of genes (y-axis) that are significantly affected by combined perturbations (x-axis) within modules (left bar chart) or between modules (right bar chart), whether additive or non-additive.

[0190] Figure 5BThis is a set of scatter plots illustrating intra-module interactions within the indicated modules. The y-axis shows the fold change in expression observed in cells with perturbations in two genes from the same module (relative to control), and the x-axis shows the expected fold change (dots) from an additive model based on two separate perturbations for each of the 1,041 genes. The slope of the first principal component (PC) (red line) and the variance (R²) of the observed double knockout explained by single knockout are labeled. 2 Module M4 is not shown due to insufficient number of double knockout cells.

[0191] Figure 5C This shows the effect in a single module (M) i ), inter-module pair (M) i :M j ;i≠j) and intra-module pairs (M i :M i A heatmap of the magnitude of the significant effect of perturbations at the (row) level on each of the 1,041 genes (columns; labeled by gene programming) (bar chart; FDR < 0.1). Bottom row: Centered average expression in control cells.

[0192] Figure 5D This is a graph showing the binarized significant effect size (FDR<0.1) of gene expression by a single perturbation from regulators M3 or M5 (rows; genes with significant interaction terms only), their additive effects (M3+M5), their interaction terms (M3:M5), and the observed combined effects (columns).

[0193] Figure 5E This is a schematic diagram illustrating an overview of the comβVAE method for predicting combined perturbations.

[0194] Figure 5F It is a set of box plots that illustrate the relationship between a single module (M) and a single module (M). i ) and module combination (M i :M j (i≠j), the distribution of the variance explained by the fold change of 1,041 genes under different Kullback-Leibler (KL) loss weights (x-axis) (y-axis; Ri≠j), 2 (This refers to 7 runs with the same hyperparameters).

[0195] Figure 5G This is a set of bar charts showing the use of single KOs from all modules (M) in the model (β = 6.0), or the use of single KOs from all modules and from one or two pairs of modules (M). i :M jWhen trained on double-KO data (x-axis) with i≠j), the variance explained by Ri in fold changes of 1,041 genes from 7 runs with the same hyperparameters in a specified inter-module combination (top label) is: 2 The distribution of the median (Q1, Q2, Q3) along the y-axis is shown in the boxes. The boxes represent the first quartile (Q1), second quartile (Q2, median), and third quartile (Q3), while the bottom and top whiskers represent the intervals [Q1 - 1.5IQR, Q1] and [Q2, Q3], respectively. 3, Q3+1.5IQR).

[0196] Figure 6A It is a heatmap showing the significant MAGMA Z-scores (bar graph; for each trait; Bonferroniα < 0.1) of immune disease traits (columns) of the M6 ​​E3 family genes (rows), with at least one significant score.

[0197] Figure 6B This is a set of heatmaps showing the significance (-log) of heritability enrichment of different immune traits (columns) associated with genetic disease risk in human immune diseases in each gene program (row), based on the intersection (left) or MAGMA (right) of sc-linker analysis combined with Roadmap and ABC gene enhancer linking strategies via single nucleotide polymorphism (SNP) annotation, and in each gene program (row). 10 (p-value), dotted shaded area, and effect size (dotted size).

[0198] Figure 6C This is a heatmap showing gene programs expressed during the progression of immune diseases in both immune and non-immune cells. A bar chart shows the enrichment (columns) of gene programs (rows) targeting cell type-specific disease progression programs in humans across different cell types and diseases.

[0199] Figure 6D This is a heatmap showing gene programs expressed during the progression of immune diseases in both immune and non-immune cells. It also shows enrichment (bar chart) of gene programs (columns) of cell type-specific disease progression programs in dendritic cells and macrophages in ulcerative colitis (UC), fibrosis, asthma, and COVID-19.

[0200] Figure 6E This is a heatmap showing the regulatory coefficients (bar charts) of the effect of perturbation regulators (rows) on the expression of genes (columns) with rare variants associated with inflammatory bowel disease (IBD). Figure 2C (The model), these rare variants also have at least one significantly regulated E3 family member.

[0201] Figure 6FThis shows the significance (-log) of heritability enrichment of gene programs (lines) for Crohn's disease (CD) or IBD based on rare (CD:SAIGE-GENE) or common (IBD:MAGMA and CD:MAGMA) variants. 10 A graph of (p-value), (dotted shaded area), and effect size (dotted area).

[0202] Figure 7 This is a diagram illustrating the DC lifecycle regulated by E3 ligase. ICA factors and their key regulators grouped in each DC lifecycle stage are shown in boxes. Bottom: UMAP embeddings of cell outlines colored by expression scores of migration-related factors (bar chart). Figure 1C middle).

[0203] Figure 8A This is a graph showing the forward scattering (x-axis) versus the side scattering (y-axis) of the selected active perturbation BMDC.

[0204] Figure 8B This is a graph showing the forward scattering (x-axis) versus the side scattering (y-axis) of the selected single-perturbation BMDC.

[0205] Figure 8C Selected mKate2 + GFP + GFP fluorescence in cells (x-axis; Cas9 mouse cells) and mKate2 fluorescence (y-axis; Perturb-Seq vector).

[0206] Figure 8D This is a graph showing the distribution of mKate2 expression (x-axis) in sorted live single cells.

[0207] Figure 8E This is a diagram illustrating the detailed PerturbDecode workflow.

[0208] Figure 8F This is a graph showing the cumulative distribution function (CDF) (y-axis) of Pearson r (x-axis) between the effect sizes of guides targeting the same gene, different genes, one gene and a non-target control, or one gene and an inter-gene control.

[0209] Figure 8G This is a graph showing the distribution of the number of genes (y-axis) (out of 6,685 tested genes) that were significantly affected (FDR < 0.1) by non-targeted controls, inter-gene controls, or targeted guides (guides that bind to the same gene) (x-axis). ****P < 2.2*10 -16 One-sided Wilcoxon rank-sum test.

[0210] Figure 8HThis is a graph showing the magnitude of the significant effect of the perturbation on itself and the other 544 targets (columns) among the 6,685 genes with tested expression in 544 targets (rows). (Bar graph; negative / positive fold change; FDR < 0.1) Rows and columns are sorted alphabetically. 137 out of 539 genes significantly negatively affected their own expression (diagonal).

[0211] Figure 8I This is a scatter plot showing the number of genes whose expression was significantly affected (FDR < 0.1) by perturbations of each of the 849 perturbation genes (from 13,811 detected genes) (y-axis) and the average expression of these perturbation genes (x-axis, normalized log1p). Pearson r and significance are in the top left corner.

[0212] Figure 8J This is a set of violin plots showing the distribution of the number (y-axis) of genes significantly affected (“expressed”) or unaffected (“not expressed”) by perturbations of genes among 13,811 genes examined (FDR < 0.1). ****P-value < 10 -4 One-sided Wilcoxon rank-sum test.

[0213] Figure 9A It is a graph showing the average expression (dotted shaded, average normalized log1p expression) and the fraction of cells expressing differentially expressed genes (columns) in each of the 10 cell clusters (rows) (dot size).

[0214] Figure 9B This is a graph showing the average expression (dotted shades, average normalized log1p expression) and the fraction of expressing cells (dot size) of differentially expressed genes (rows) in the DC2 marker genes (columns).

[0215] Figure 9C This is a graph showing the average expression (dotted shades, average normalized log1p expression) and the fraction of expressing cells (dot size) of differentially expressed genes (rows) in mDC marker genes (columns).

[0216] Figure 9D This is a graph showing the average expression (dotted shades, average normalized log1p expression) and the fraction of expressing cells (dot size) of differentially expressed genes (rows) in the DC1 marker gene (columns).

[0217] Figure 9E This is a graph showing the average expression (dotted shades, average normalized log1p expression) and the fraction of expressing cells (dot size) of differentially expressed genes (rows) in pDC marker genes (columns).

[0218] Figure 9FThis is a graph showing the average expression (dotted shades, average normalized log1p expression) and the fraction of expressing cells (dot size) of differentially expressed genes (rows) in the M1 marker gene (columns).

[0219] Figure 9G This is a graph showing the average expression (dotted shades, average normalized log1p expression) and the fraction of expressing cells (dot size) of differentially expressed genes (rows) in the M2 marker genes (columns).

[0220] Figure 9H These are 519,535 cell outlines colored according to DC (DC1+DC2+mDC) gene characteristic scores (e.g. Figure 1C UMAP embedding in (China).

[0221] Figure 9I It consists of 519,535 cell outlines colored according to macrophage characteristic scores (e.g. Figure 1C UMAP embedding in (China).

[0222] Figure 9J UMAP embeddings of BMDC contours from 3,655 undisturbed, unstimulated and 4,027 undisturbed and LPS-stimulated (3 hours) subjects, stained by treatment.

[0223] Figure 9K The UMAP embeddings of BMDC profiles from 3,655 unperturbed and unstimulated and 4,027 unperturbed and LPS-stimulated (3 hours) BMDCs are stained according to the inferred cell cycle stage.

[0224] Figure 9L The UMAP embeddings of BMDC profiles from 3,655 unperturbed, unstimulated and 4,027 unperturbed and LPS-stimulated (3 hours) models are presented, according to... Figure 1C The top 100 upregulated genes in cluster 1 are characterized by feature scoring and coloring.

[0225] Figure 9M The UMAP embeddings of BMDC profiles from 3,655 unperturbed, unstimulated and 4,027 unperturbed and LPS-stimulated (3 hours) models are presented, according to... Figure 1C The top 100 upregulated genes in cluster 2 are characterized by feature scoring and coloring.

[0226] Figure 9N The UMAP embeddings of BMDC profiles from 3,655 unperturbed, unstimulated and 4,027 unperturbed and LPS-stimulated (3 hours) models are presented, according to... Figure 1C The top 100 upregulated genes in cluster 3 are characterized by feature scoring and coloring.

[0227] Figure 9OThe UMAP embeddings of BMDC profiles from 3,655 unperturbed, unstimulated and 4,027 unperturbed and LPS-stimulated (3 hours) models are presented, according to... Figure 1C The top 100 upregulated genes in cluster 4 are characterized by feature scoring and coloring.

[0228] Figure 9P The UMAP embeddings of BMDC profiles from 3,655 unperturbed, unstimulated and 4,027 unperturbed and LPS-stimulated (3 hours) models are presented, according to... Figure 1C The top 100 upregulated genes in cluster 5 are characterized by feature scoring and coloring.

[0229] Figure 9Q The UMAP embeddings of BMDC profiles from 3,655 unperturbed, unstimulated and 4,027 unperturbed and LPS-stimulated (3 hours) models are presented, according to... Figure 1C The top 100 upregulated genes in cluster 6 are characterized by feature scoring and coloring.

[0230] Figure 9R The UMAP embeddings of BMDC profiles from 3,655 unperturbed, unstimulated and 4,027 unperturbed and LPS-stimulated (3 hours) models are presented, according to... Figure 1C The top 100 upregulated genes in cluster 7 are characterized by feature scoring and coloring.

[0231] Figure 9S The UMAP embeddings of BMDC profiles from 3,655 unperturbed, unstimulated and 4,027 unperturbed and LPS-stimulated (3 hours) models are presented, according to... Figure 1C The top 100 upregulated genes in cluster 8 are characterized by feature scoring and coloring.

[0232] Figure 9T The UMAP embeddings of BMDC profiles from 3,655 unperturbed, unstimulated and 4,027 unperturbed and LPS-stimulated (3 hours) models are presented, according to... Figure 1C The top 100 upregulated genes in cluster 9 are characterized by feature scoring and coloring.

[0233] Figure 9U The UMAP embeddings of BMDC profiles from 3,655 unperturbed, unstimulated and 4,027 unperturbed and LPS-stimulated (3 hours) models are presented, according to... Figure 1C The top 100 upregulated genes in cluster 10 are characterized by feature scoring and coloring.

[0234] Figure 9V The UMAP embeddings of BMDC profiles from 3,655 unperturbed, unstimulated and 4,027 unperturbed and LPS-stimulated (3 h) BMDCs are stained according to their predicted major cell subtypes.

[0235] Figure 9WThis is a bar chart showing the percentage of cells (y-axis) of each of the four major subtypes in the data (x-axis) filtered (legend) for unperturbed, unstimulated, unperturbed LPS-stimulated, and perturbed LPS-stimulated data. *P<2.2*10 -16 One-sided Fisher exact test.

[0236] Figure 9X It is a heatmap, which shows, for example... Figure 1C The ratio of enrichment or depletion (FDR < 0.15, one-sided Fisher exact test) of cells with perturbation genes in the major subtypes (columns) during the cell cycle (rows) (bar chart).

[0237] Figure 9Y It is a heatmap, which shows, for example... Figure 1C The ratio (bar chart) of the enrichment or depletion (FDR < 0.15, one-sided Fisher exact test) of cells with perturbation genes (rows) in 10 cell clusters (columns) during the cell cycle stage.

[0238] Figure 10A Cell outlines colored according to the expression score of the GP1 program gene (e.g.) Figure 1C UMAP embedding in (China).

[0239] Figure 10B Cell outlines colored according to the gene expression score of the GP2 program (e.g.) Figure 1C UMAP embedding in (China).

[0240] Figure 10C Cell outlines colored according to the expression score of genes in the GP3 program (e.g.) Figure 1C UMAP embedding in (China).

[0241] Figure 10D Cell outlines colored according to the gene expression score of the GP4 program (e.g.) Figure 1C UMAP embedding in (China).

[0242] Figure 10E Cell outlines colored according to the expression score of the GP5 program gene (e.g.) Figure 1C UMAP embedding in (China).

[0243] Figure 10F Cell outlines colored according to the expression score of the GP6 program gene (e.g.) Figure 1C UMAP embedding in (China).

[0244] Figure 10G Cell outlines are colored according to the gene expression score of the GP7 program (e.g., Figure 1C UMAP embedding in (China).

[0245] Figure 10H Cell outlines are colored according to the gene expression score of the GP8 program (e.g., Figure 1C UMAP embedding in (China).

[0246] Figure 10I Cell outlines colored according to the expression score of genes in the GP9 program (e.g.) Figure 1C UMAP embedding in (China).

[0247] Figure 10J Cell outlines are colored according to the gene expression score of the GP10 program (e.g., Figure 1C UMAP embedding in (China).

[0248] Figure 10K Cell outlines are colored according to the gene expression score of the GP11 program (e.g., Figure 1C UMAP embedding in (China).

[0249] Figure 10L This is a pair of heatmaps showing the Jaccard index (left) and score overlap (right) between each gene program (row, "A") and programs in early small perturb-seq screening of 24 TFs in LPS-stimulated BMDCs (Dixit et al., Cell, 167:1853-1866.e17, 2016) (left, column, "B") or DC subset characteristics (Maier et al., Nature, 580:257-262, 2020) (right, column, "B").

[0250] Figure 10M This is a set of violin plots showing the distribution of programmed scores (GP1-11; y-axis) for DC1-like, DC2-like, mDC-like, and macrophage-like cell subsets (x-axis). *P<0.05 One-to-many one-sided Wilcoxon rank-sum test.

[0251] Figure 11A This is a graph showing the binarized regulatory effect (blue: negative; red: positive) of perturbing each of the 60 E3 ligases in the model, which significantly affects the expression of at least one other E3 ligase among the 60 E3 ligases. Module membership markers are on the left and at the top. The negative impact of KO on its own RNA levels is not shown.

[0252] Figure 11B This is a graph showing the binarized regulatory effect (negative or positive) of perturbing each of the 60 E3 ligases in the model for 15 E3 ligases that both affect and are affected by another E3. This perturbation significantly affects the expression of at least one other E3 ligase among the 60 E3 ligases. Module membership markers are on the left and top. The negative impact of KO on its own RNA levels is shown.

[0253] Figure 11C It is a set of UMAP embeddings of cell contours (e.g. Figure 1C (Middle) Cells are colored according to the Gaussian nuclear density estimate of cells with a control guide (top left) or a guide with the target gene for each module (top label).

[0254] Figure 11D It is a supervised UMAP embedding (e.g., using the cofunctional modules of cells to assign response markers to the outlines of DC2.1, DC2.2, and DC2.3 cells) Figure 3C (in the middle), colored according to the difference in Z-scores of macrophage and DC characteristics.

[0255] Figure 11E It is a stacked bar chart, which shows the values ​​belonging to Figure 1C The percentage of cells with a target gene guide in each module of each cell cluster (x-axis) (y-axis).

[0256] Figure 11F It is a stacked bar chart, which shows the guide-targeting genes in each module. Figure 1C The percentage of cells in each cell cluster (x-axis) (y-axis).

[0257] Figure 11G This is a graph showing the physical interactions (grey; experimental score >0, STRING DB) or lack of physical interactions (white) between each pair of 165 E3 ligases in 329 regulatory factors (rows, columns). Shading indicates whether the regulatory maps of physically interacting genes have a significant (P<0.05) positive correlation, a significant (P<0.05) negative correlation, or no significant correlation. Genes are sorted by module membership (shaded at the top and left).

[0258] Figure 11H The diagram shows the physical interactions between the NFkB signaling pathway components included in the regulation model (nodes) (edges: STRING DB experimental score > 0), colored according to the significance (P < 0.05) of their perturbation effect, either positively or negatively correlated.

[0259] Figure 11I These are a pair of charts showing: Top: Physical interactions (grey; experimental score >0, STRING DB; coloring code such as G) between each perturbed CLR E3 ligase (rows) and its CLR complex members (including adaptor domain proteins) (columns) or the absence of physical interactions (white). Columns are sorted by CLR physical complex / interaction (boxes and dashed lines). Bottom: Same as top, except showing all significant covariances, without considering evidence of interactions.

[0260] Figure 11J It is a heatmap showing the inferred activity score (rbar) of 109 TFs (columns) whose target genes were significantly (FDR<0.1) induced or inhibited (by at least 10 perturbations) when each of the 156 E3 and related genes (rows) was perturbed (affecting at least 10 of the 109 TFs).

[0261] Figure 11K It is a set of Venn diagrams that show the intersection between TF targets (DoRothEA), E3 expression targets, and gene programs.

[0262] Figure 12A It is a graph showing the moderating factors (rows) associated with each factor (column) through their outlier weights in the mixing matrix.

[0263] Figure 12B It is a graph showing the member genes (columns) associated with each factor (column) loaded by the outlier values ​​in the matrix estimated from the source signal.

[0264] Figure 12C This is a plot showing the “gn”-master criterion for the Ladle estimates (y-axis) of unseen perturbation responses in randomly sampled ICA decompositions with different numbers of components (x-axis).

[0265] Figure 12D This shows the explained variance (R²) after matrix reconstruction of the estimated components in an unseen perturbation response from a random sample of ICA decompositions with varying numbers of components (x-axis). 2 A graph (y-axis).

[0266] Figure 12E It is a set of box plots that show the distribution of the explained variance (y-axis) in an unseen perturbation response of a random sample of ICA decomposition with different numbers of components (x-axis).

[0267] Figure 12F It is a set of UMAP embeddings (e.g., cell outlines colored according to the expression score (label at the top) of each subfactor) Figure 1C middle).

[0268] Figure 12G It is a heatmap that shows the Jaccard index (bar chart) for each pair of factors (columns and rows) of genes with outlier loading in a matrix based on source signal estimation.

[0269] Figure 12H It is a heatmap that shows the Jaccard index (bar chart) for each pair of factors (columns and rows) of moderating factors with outlier weights in the mixture matrix for each factor.

[0270] Figure 13A It is a heatmap showing the number of cells in the E3 screening (bars, numbers), where guide pairs with the target gene are in the same or paired modules (rows, columns).

[0271] Figure 13B It is a graph showing the number of significant interaction terms (FDR < 0.1, y-axis) on the expression of each gene (x-axis) from combined perturbations of all intra- and inter-module interactions.

[0272] Figure 13C This shows that due to a module (M) i A single perturbation in a gene along the x-axis can significantly affect expression, or it may be due to a single perturbation in the same gene (M). i :M i (x-axis) or different (M) i :M j A stacked bar chart of the number of target genes (y-axis, 1,041 in the regulatory model) with significant interaction terms in two genes of the module (i≠j, x-axis).

[0273] Figure 13D This demonstrates the process using two different modules (M) i M j The binary significant effect (FDR < 0.1) (positive or negative) of a single perturbation in the regulators of (i ≠ j) on the expression of genes (rows, only genes with significant interaction terms), and their additive effect (M i +M j ), and their interaction terms (M) i :M j A graph showing the observed effects (columns). Membership in the gene program is labeled on the left.

[0274] Figure 13E This demonstrates the process using two different modules (M) i M j The binary significant effect (FDR < 0.1) (positive or negative) of a single perturbation in the regulators of (i ≠ j) on the expression of genes (rows, only genes with significant interaction terms), and their additive effect (M i +M j ), and their interaction terms (M) i :M j A graph showing the observed effects (columns). Membership in the gene program is labeled on the left.

[0275] Figure 13FThis is a set of scatter plots showing the fold change in gene expression (y-axis) observed after inter-module combinational perturbations or (x-axis) predicted by an additive model for each of the 1,041 genes (points). R 2 : Variance explained by the observed multiple change; MAE: Mean absolute error of the prediction.

[0276] Figure 13G This is a set of scatter plots showing the fold change in gene expression (y-axis) observed after inter-module combinatorial perturbations or (x-axis) predicted by an additive model for each of the 1,041 genes with significant (FDR < 0.1) inter-module interaction terms. R 2 : Variance explained by the observed multiple changes.

[0277] Figure 13H This is a set of scatter plots showing the fold change in gene expression (y-axis) observed after inter-module combinatorial perturbations or (x-axis) predicted by an additive model for each of the 1,041 genes with non-significant (FDR>=0.1) inter-module interaction terms. R 2 : Variance explained by the observed multiple changes.

[0278] Figure 14A This is a set of scatter plots showing the fold change in gene expression observed (y-axis) or predicted (x-axis) by comβVAE after inter-module combination perturbation (y-axis) for each of the 1,041 genes (points) or for genes with only significant (B, FDR < 0.1) inter-module interaction terms. Diagonal entries reflect predictions for single knockout.

[0279] Figure 14B This is a set of box plots showing the fold change in gene expression observed (y-axis) or predicted (x-axis) by comβVAE after inter-module combination perturbation (y-axis) for each of 1,041 genes with significant (FDR < 0.1) inter-module interaction terms. All boxes in the box plots represent the first quartile (Q1), second quartile (Q2, median), and third quartile (Q3), and the bottom and top whiskers represent the intervals [Q1 - 1.5IQR, Q1] and [Q...]. 3, Q3+1.5IQR).

[0280] Figure 14C This is a set of scatter plots showing the performance of each module (M) over 7 runs with the same hyperparameters. i ) or module combination (M i :M j,i≠j)(x-axis), the explained variance of the comβVAE model predictions (top, y-axis, Ri) 2 The distribution of mean absolute error (bottom, y-axis, MAE).

[0281] Figure 14D This is a set of box plots that show the performance of each module (M) over 7 runs with the same hyperparameters. i ) or module combination (M i :M j The distribution of the explained variance (D, y-axis) of the comβVAE model under different KL loss weight values ​​(x-axis), i≠j).

[0282] Figure 14E This is a set of box plots showing the performance of the model (β = 6.0) in 7 runs with the same hyperparameters, using only single perturbation cells from all modules (M) or single perturbation cells from all modules and one or two pairs of modules (M). i :M j When training with data from double-perturbed cells (i≠j)(x-axis), the explained variance (y-axis, Ri) of fold changes in the indicated inter-module combinations (labels at the top of the figure) is calculated. 2 The distribution of ).

[0283] Figure 14F This is a set of box plots showing the explained variance (y-axis) of the fold change in each module pair (plot) when the comβVAE model is trained with different KL loss weight values ​​(x-axis) and trained with only single-perturbation cells (red) or with both single-perturbation and double-perturbation cells for a specific module pair (plot) (green: M3M5, blue: M5M6, purple: M3M5 and M5M6).

[0284] Figure 14G This is a set of box plots showing the explained variance (y-axis) of fold change in selected module pairs with a relatively high number of genes having significant inter-module interaction terms (column headers) when learning comβVAE under different KL loss weight values ​​(x-axis) and training with only single-perturbation cells or with single-perturbation and double-perturbation cells with specific module pairs (row labels). Detailed Implementation

[0285] I. Definition

[0286] Unless otherwise defined, all technical terms, symbols, and other scientific terms used herein are intended to have the meaning commonly understood by one of ordinary skill in the art to which this invention pertains. In some cases, for clarity and / or ease of reference, terms with commonly understood meanings are defined herein, and these definitions contained herein are not necessarily to be construed as indicating a significant difference from the commonly understood meaning in the art compared to definitions of terms commonly understood in the prior art.

[0287] As used herein, the term "approximately" refers to a common range of error for a corresponding value that is readily known to those skilled in the art. References to "approximately" values ​​or parameters herein include (and describe) aspects relating to the value or parameter itself.

[0288] As used herein, unless the context clearly indicates otherwise, the singular forms “an,” “a,” and “the / said” include the plural objects referred to. For example, reference to “an isolated peptide” means one or more isolated peptides.

[0289] Throughout the specification and claims, the word “comprising” or variations thereof, such as “comprises” or “comprising”, should be understood to imply the inclusion of the stated integers or groups of integers, but not to exclude any other integers or groups of integers.

[0290] The terms “patient,” “subject,” or “individual,” which may be used interchangeably in this article, refer to a human patient.

[0291] "Effective amount" refers to the amount of a medicine (e.g., a therapeutic agent) that effectively produces therapeutic / preventive benefits (e.g., as described herein) that are not outweighed by unwanted / undesirable side effects.

[0292] The term "pharmaceutical formulation" refers to a preparation that is in a form that allows for the effective bioactivity of one or more active ingredients and does not contain any additional components that would have unacceptable toxicity to a subject to whom the formulation will be administered. Such formulations are sterile. In one embodiment, the formulation is for intravenous (iv) administration. In another embodiment, the formulation is for subcutaneous (sc) administration.

[0293] The term "natural sequence" in this article refers to a protein that contains the amino acid sequence of a naturally occurring protein, including naturally occurring variants of the protein. The terminology used herein includes proteins isolated from or recombinantly produced from their natural sources.

[0294] Unless otherwise specified, as used herein, the term "protein" means any naturally occurring protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term includes "full-length" unprocessed proteins, any form of protein produced through cellular processing. The term also covers naturally occurring protein variants, such as splice variants or allelic variants, such as amino acid substitution mutations or amino acid deletion mutations. The term also includes segregated regions or domains of proteins, such as extracellular domains (ECDs).

[0295] "Isolated" proteins or peptides are those that have been separated from components of their natural environment. In some respects, proteins or peptides are purified to a purity greater than 95% or 99% by means of, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reversed-phase HPLC).

[0296] "Isolated" nucleic acids refer to nucleic acid molecules that have been separated from components of their natural environment. Isolated nucleic acids include nucleic acid molecules that are contained in cells that normally contain nucleic acid molecules, but which are located outside the chromosome or at a chromosomal location different from their natural chromosomal location.

[0297] As used herein, a “regulator” is an agent that modulates (e.g., increases, decreases, activates, or inhibits) a given biological activity, such as a downstream activity resulting from an interaction or an interaction between two proteins (e.g., a direct or indirect interaction). Regulators or candidate regulators can be, for example, small molecules, antibodies (e.g., bispecific or multispecific antibodies), antigen-binding fragments (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bispecific antibodies, linear antibodies, scFv, ScFab, VH domain, or VHH domain), peptides, mimics, antisense oligonucleotides, or repressive nucleic acids (e.g., antisense oligonucleotides (ASO) or small interfering RNA (siRNA)).

[0298] "Increase" or "activation" refers to the ability to cause an overall increase, such as an increase of 20% or more, 50% or more, or 75%, 85%, 90%, 95% or more. In some respects, increase or activation can refer to the downstream activity of protein-protein interactions.

[0299] "Reduction" or "inhibition" refers to the ability to cause an overall decrease, such as a decrease of 20% or more, 50% or more, or 75%, 85%, 90%, 95% or more. In some respects, reduction or inhibition can refer to the downstream activity of protein-protein interactions.

[0300] “Affinity” refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., a receptor) and its binding partner (e.g., a ligand). Unless otherwise stated, as used herein, “binding affinity” refers to intrinsic binding affinity, which reflects the 1:1 interaction between members of a binding pair (e.g., receptor and ligand). The affinity of molecule X for its partner Y can generally be determined by the dissociation constant (K0). D Affinity can be measured using conventional methods known in the art, including those described herein.

[0301] As used herein, "complex" or "composite" refers to the association of two or more molecules interacting with each other by non-peptide bonds and / or forces (e.g., van der Waals forces, hydrophobic forces, hydrophilic forces). In one aspect, a complex is a heteropolymer. It should be understood that, as used herein, the terms "protein complex" or "peptide complex" include complexes having a non-protein entity (e.g., including but not limited to chemical molecules such as toxins or detection agents) conjugated to a protein complex.

[0302] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells in which exogenous nucleic acids have been introduced, including progeny cells. Host cells include “transfected cells,” “transformed cells,” and “transformants,” which include primary transformed cells and progeny derived from those primary transformed cells, regardless of passage number. Progeny cells may not be identical to the nucleic acid contents of the parent cells and may contain mutations. This article includes mutant progeny with the same function or biological activity as those screened or selected from the original transformed cells. In some respects, host cells are stably transformed by exogenous nucleic acids. In others, host cells are transiently transformed by exogenous nucleic acids.

[0303] As used herein, the term "vector" refers to a nucleic acid molecule capable of carrying another nucleic acid linked to it. This term includes vectors that function as self-replicating nucleic acid structures, as well as vectors incorporated into the genome of a host cell into which they have been introduced. Some vectors are capable of directing the expression of the nucleic acid to which they are operatively linked. Such vectors are referred to herein as "expression vectors."

[0304] The term “antibody” is used in the broadest sense and encompasses a wide variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (e.g., double Fab), as long as they exhibit the desired antigen-binding activity.

[0305] An "antigen-binding fragment" or "antibody fragment" refers to a molecule other than a complete antibody that contains a portion of the complete antibody that binds to the antigen bound by the complete antibody. Examples of antigen-binding fragments include, but are not limited to: double Fab; Fv; Fab; Fab, Fab'-SH; F(ab')2; bisomatic antibodies; linear antibodies; single-chain antibody molecules (e.g., scFv, scFab); and multispecific antibodies formed from antibody fragments.

[0306] A "single-domain antibody" is an antibody fragment containing all or part of the heavy chain variable domain or all or part of the light chain variable domain. In some respects, single-domain antibodies are human single-domain antibodies (see, for example, U.S. Patent No. 6,248,516B1). Examples of single-domain antibodies include, but are not limited to, VHH.

[0307] The “Fab” fragment is an antigen-binding fragment produced by papain digestion of an antibody and consists of the intact L chain, a variable region (VH) of the H chain, and a first constant region (CH1) of a heavy chain. Papain digestion of the antibody produces two identical Fab fragments. Pepsin treatment of the antibody produces a single large F(ab')2 fragment, which roughly corresponds to two Fab fragments linked by disulfide bonds, possessing divalent antigen-binding activity and still capable of cross-linking antigens. The Fab' fragment differs from the Fab fragment in that it has residues added to the carboxyl terminus of the CH1 domain, these residues containing one or more cysteine ​​residues from the antibody hinge region. Fab'-SH is the designation used herein for Fab' fragments in which the cysteine ​​residues of the constant region have free thiol groups. The F(ab')2 antibody fragment was originally produced as a pair of Fab' fragments with hinge cysteine ​​residues in between. Other chemical conjugations of antibody fragments are also known.

[0308] The term "Fc region" used herein is used to define the C-terminal region of the immunoglobulin heavy chain, which includes both the native sequence Fc region and variant Fc regions. Although the boundaries of the immunoglobulin heavy chain Fc region may vary, the human IgG heavy chain Fc region is generally defined as extending from the amino acid residue at position Cys226 or from Pro230 to the carboxyl terminus of the heavy chain. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) may be removed, for example, during antibody production or purification or by recombinantly designing the nucleic acid encoding the antibody heavy chain. Therefore, compositions of complete antibodies may include antibody populations with all Lys447 residues removed, antibody populations with Lys447 residues not removed, and antibody populations having mixtures containing and without Lys447 residues.

[0309] "Fv" consists of a tight, non-covalently associated dimer of a heavy-chain variable region domain and a light-chain variable region domain. The folding of these two domains generates six hypervariable rings (three rings each from the H and L chains), which contribute amino acid residues to achieve antigen binding, thus giving the antibody antigen-binding specificity. However, even a single variable domain (or half of Fv, containing only three antigen-specific CDRs) can recognize and bind antigens, although its affinity is often lower than that of the intact binding site.

[0310] The terms “full-length antibody,” “intact antibody,” and “all antibody” are used interchangeably herein to refer to antibodies having a structure substantially similar to that of natural antibodies or having a heavy chain containing an Fc region as defined herein.

[0311] A "single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment containing VH and VL antibody domains linked to a single polypeptide chain. Preferably, the scFv polypeptide further includes a polypeptide linker between the VH and VL domains, enabling the scFv to form the desired antigen-binding structure. For a review of scFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, edited by Rosenburg and Moore, Springer-Verlag, New York, pp. 269-315 (1994); Malmborg et al., J. Immunol. Methods 183:7-13, 1995.

[0312] The term "small molecule" refers to any molecule with a molecular weight of about 2,000 Daltons or less, such as about 1,000 Daltons or less. In some respects, small molecules are organic small molecules.

[0313] As used herein, the term "molecular mimic" or "molecular mimic" refers to a polypeptide that is sufficiently similar in conformation and / or binding ability (e.g., secondary structure, tertiary structure) to a binding pair of a given polypeptide or a portion thereof to bind to the binding pair of the polypeptide. The mimic may bind to the binding pair with an affinity equal to, less than, or greater than that of the polypeptide it mimics. The molecular mimic may or may not have significant amino acid sequence similarity to the polypeptide it mimics. The mimic may be naturally occurring or engineered. In some respects, the mimic is a mimic of a binding pair member. In other respects, the mimic is a mimic of another protein that binds to a binding pair member. In some respects, the mimic can perform all the functions of the mimicked polypeptide. In other respects, the mimic does not perform all the functions of the mimicked polypeptide.

[0314] As used herein, the term "permissible binding conditions" for two or more proteins refers to conditions (e.g., protein concentration, temperature, pH, salt concentration) under which the two or more proteins will interact in the absence of a regulator or candidate regulator. Permissible binding conditions may vary from individual protein to protein and may vary from protein-protein interaction assays (e.g., surface plasmon resonance assays, biolayer interference assays, enzyme-linked immunosorbent assays (ELISA), extracellular interaction assays, and cell surface interaction assays).

[0315] The "percentage of amino acid sequence identity (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to those in the reference polypeptide sequence after aligning the candidate sequence with the reference polypeptide sequence and introducing vacancies (if necessary) to achieve the maximum percentage of sequence identity, without considering any conserved substitutions as part of the sequence identity. Alignment used to determine the percentage of amino acid sequence identity can be performed in various ways within the scope of the art, such as using publicly available computer software, such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm required to achieve maximum alignment across the full length of the sequences being compared. However, for the purposes of this document, the sequence comparison computer program ALIGN-2 is used to generate the value of the amino acid sequence identity %. The ALIGN-2 sequence comparison computer program was developed by Genentech, Inc., and the source code has been submitted with user documentation to the US Copyright Office, Washington DC, 20559, where it is registered under US Copyright Registry No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California) or can be compiled from source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and remain unchanged.

[0316] When using ALIGN-2 for amino acid sequence comparison, the percentage of identity between a given amino acid sequence A and or with respect to a given amino acid sequence B (which can be alternatively expressed as a given amino acid sequence A having or containing a percentage of identity with or with respect to a given amino acid sequence B) is calculated as follows:

[0317] 100 multiplied by the fraction X / Y

[0318] Where X represents the number of amino acid residues that were scored as identical matches by the sequence alignment program ALIGN-2 in the alignment of A and B, and Y represents the total number of amino acid residues in B. It should be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the amino acid sequence identity % between A and B will not be equal to the amino acid sequence identity % between B and A. Unless otherwise specifically stated, all amino acid sequence identity % values ​​used herein were obtained using the ALIGN-2 computer program as described in the preceding paragraph.

[0319] As used herein, “treatment” (and its grammatical variations, such as “treat” or “treating”) refers to a clinical intervention that attempts to alter the natural course of the individual being treated, and may be for prevention or during the course of clinicopathological development. The desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease (e.g., preventing disease or disorders or their symptoms associated with dendritic cells and / or inflammation), reducing or preventing secondary infections in patients with infections (e.g., reducing or preventing secondary infections of nerve tissue, immune cells, lymphoid tissue, and / or lung tissue), alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, slowing the rate of disease progression, improving or mitigating the disease state, and alleviating or improving prognosis.

[0320] The "pathology" of a disease or symptom includes all phenomena that impair a patient's health.

[0321] "Amelioration / ameliorating," "alleviation / alleviating," or their equivalents refer to therapeutic treatments and preventative or preventive measures aimed at improving, preventing, alleviating (reducing), reducing, or suppressing a disease or condition, such as those related to dendritic cells and / or inflammation. Those requiring treatment include people who already have a disease or condition, people who are prone to developing a disease or condition, or people whose disease or condition requires prevention.

[0322] As used herein, the term "treatment" (or "treating") refers to a clinical intervention designed to alter the natural course of the treated individual or cells in a clinicopathological process. Ideal treatment outcomes include slowing or reducing the rate of disease progression, mitigating or alleviating disease states, and alleviating or improving prognosis. For example, an individual is considered successfully "treated" if one or more symptoms associated with cancer, an inflammatory disease, or an autoimmune disease are relieved or eliminated. Indicators of successful cancer treatment include, but are not limited to, reducing the proliferation of cancer cells (or destroying cancer cells), reducing symptoms caused by the disease, improving the quality of life of a person with the disease, reducing the dosage of other medications required to treat the disease, slowing disease progression, and / or prolonging individual survival. Treatments in this article specifically include adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (e.g., locally advanced cancer therapy), and metastatic cancer therapy. Treatment can be first-line (e.g., the patient may not have previously been treated or received prior systemic therapy) or second-line or subsequent treatment.

[0323] As used herein, “in combination with” or “in combination with” means the application of another treatment modality in addition to one treatment modality, such as a treatment regimen that includes the application of modulators or modified cells as provided herein, along with one or more additional agents. Thus, “in combination with” means the application of another treatment modality before, during, or after the administration of one treatment modality to a patient.

[0324] The terms “cancer” and “cancerous” refer to or describe a physiological condition in mammals typically characterized by uncontrolled cell growth. Cancer includes solid tumor cancers and non-solid tumor cancers, as well as locally advanced or metastatic cancers (e.g., locally advanced or metastatic tumors). Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include, but are not limited to, urothelial carcinoma (UC), including locally advanced and metastatic UC (mUC), bladder cancer (e.g., muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC), e.g., BCG-refractory NMIBC), MIBC urothelial bladder cancer (UBC); kidney or renal cancer (e.g., renal cell carcinoma (RCC)); urinary tract cancer; lung cancer, such as small cell lung cancer (SCLC) (which includes extensive-stage SCLC (ES-SCLC)) and non-small cell lung cancer (NSCLC) (which includes squamous NSCLC or non-squamous NSCLC). CLC, including locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)); lung adenocarcinoma or squamous cell carcinoma (e.g., epithelial squamous cell carcinoma (e.g., lung squamous cell carcinoma)); pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC); head and neck cancer (e.g., SCCHN, e.g., recurrent / metastatic PD-L1 positive SCCHN and head and neck squamous cell carcinoma (HNSCC)); ovarian cancer (OC); esophageal cancer; peritoneal cancer; hepatocellular carcinoma; gastric cancer (GC) (e.g., gastric esophageal cancer). Cancers of the ductal junction (GEJ) or stomach, including gastrointestinal cancers and gastrointestinal stromal cancers; glioblastoma; urinary tract cancers; liver cancer; breast cancer, such as HER2+ breast cancer and triple-negative breast cancer (TNBC (e.g., early TNBC (eTNBC), which is estrogen receptor-negative (ER-), progesterone receptor-negative (PgR-), and HER2-negative (HER2-))); prostate cancer, such as castration-resistant prostate cancer (CRPC); peritoneal cancer; hepatocellular carcinoma; stomach cancer or gastric cancer, including gastrointestinal cancers and gastrointestinal stromal cancers; pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)); Glioblastoma; cervical cancer (e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, such as metastatic and / or recurrent PD-L1 positive cervical cancer); ovarian cancer; liver cancer (e.g., hepatocellular carcinoma (HCC), such as locally advanced or metastatic HCC and / or unresectable HCC); liver cancer; colon cancer; rectal cancer; colorectal cancer (CRC; e.g., CRC with low microsatellite stability (MSS) and microsatellite instability (MSI-Low)); endometrial cancer or uterine cancer; salivary gland cancer; prostate cancer; vulvar cancer; thyroid cancer; liver cancer; anal cancer; penile cancer;Melanoma, including superficial spreading melanoma, malignant lentigines melanoma, acral melanoma, and nodular melanoma; multiple myeloma and B-cell lymphoma (including low-grade / follicular non-Hodgkin lymphoma (NHL); small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-cleaved cell NHL; large-volume disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenström lymphoma. Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); hairy cell leukemia; chronic myeloid leukemia (CML); post-transplant lymphoproliferative disorder (PTLD); and myelodysplastic syndromes (MDS), as well as abnormal angiogenesis associated with phakomatoses, edema (such as edema associated with brain tumors), Meigs syndrome, brain cancer, head and neck cancer, and related metastases.

[0325] "Disease" or "condition" refers to any condition that will benefit from treatment, including but not limited to conditions associated with some degree of abnormal cell proliferation, such as cancer, and conditions associated with dysregulation of inflammation and / or immune responses, such as inflammatory diseases and autoimmune diseases. Inflammatory diseases and / or autoimmune diseases include, but are not limited to, neurodegenerative diseases (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD)), arthritis, allergies, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, and Crohn's disease.

[0326] II. Regulators of Protein-Protein Interactions

[0327] In some aspects, this disclosure is characterized by regulators of protein-protein interactions; methods for identifying such regulators; and methods for treating diseases (e.g., cancer, inflammatory diseases, or autoimmune diseases) comprising administering a regulator of protein-protein interactions. In any of these aspects, protein-protein interactions can be direct interactions, such as interactions in which the interacting members are in physical contact with each other (e.g., bind to each other). Alternatively, in some aspects, protein-protein interactions are indirect interactions, such as interactions in which the interacting members are not in physical contact with each other. Indirect protein-protein interactions (e.g., perturbations of the first member of a protein-protein interaction in a biological system (e.g., an organism, tissue, or cell) have a measurable effect (e.g., affecting its expression, activity, and / or abundance) on the second member of the protein-protein interaction) by determining a causal relationship between the expression, activity, and / or abundance of the first member of the protein-protein interaction and the expression, activity, and / or abundance of the second member of the protein-protein interaction). In some aspects, proteins having indirect interactions associate in pathways or networks.

[0328] In some respects, regulators of protein-protein interactions interact directly with one or both members of the protein-protein interaction (e.g., by binding). In other respects, regulators of protein-protein interactions do not interact directly with any member of the protein-protein interaction.

[0329] In some respects, this disclosure is characterized by a regulator of the separation of the interaction between the first protein and the second protein, wherein the protein-protein interaction is a direct interaction, and the regulator causes a decrease in the binding of the first protein and the second protein relative to the binding in the absence of the regulator.

[0330] In some respects, this disclosure is characterized by a regulator of the separation of the interaction between the first protein and the second protein, wherein the protein-protein interaction is a direct interaction, and the regulator causes an increase in the binding of the first protein and the second protein relative to the binding in the absence of the regulator.

[0331] In some respects, this disclosure is characterized by a separate regulator of the interaction between a first protein and a second protein, wherein the protein-protein interaction is an indirect interaction, and the regulator causes a decrease in the downstream activity of one or both members of the protein-protein interaction relative to the downstream activity in the absence of the regulator.

[0332] In some respects, this disclosure is characterized by a separate regulator of the interaction between a first protein and a second protein, wherein the protein-protein interaction is an indirect interaction, and the regulator causes an increase in the downstream activity of one or both members of the protein-protein interaction relative to the downstream activity in the absence of the regulator.

[0333] In some respects, modifiers contain pharmaceutical carriers.

[0334] A. A regulator of the interaction between the first and second proteins.

[0335] direct interaction

[0336] In some aspects, this disclosure is characterized by a regulator of the interaction between a first protein and a second protein, wherein the protein-protein interaction is a direct interaction, and the regulator causes a decrease in the binding of the first protein to the second protein and / or the binding of the second protein to the first protein.

[0337] In some aspects, the modulator reduces the binding of the first protein to the second protein and / or the binding of the second protein to the first protein by at least 50%. In some aspects, the reduction in binding relative to the binding in the absence of the modulator is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% or 100% (i.e., the binding is eliminated), for example, a reduction of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%. In some aspects, the modulator reduces the binding of the first protein to the second protein and / or the binding of the second protein to the first protein by at least 90% (e.g., 90%-100%). In some aspects, the reduction in binding is at least 50% (e.g., 50%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%), for example, as measured by surface plasmon resonance, biolayer interference, or enzyme-linked immunosorbent assay (ELISA).

[0338] In some aspects, this disclosure is characterized by a regulator of the interaction between a first protein and a second protein, wherein the protein-protein interaction is a direct interaction, and the regulator causes an increase in the binding of the first protein to the second protein and / or the binding of the second protein to the first protein.

[0339] In some aspects, the modulator increases the binding of the first protein to the second protein and / or the binding of the second protein to the first protein by at least 50%. In some aspects, the increase in binding relative to the binding in the absence of the modulator is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 100%, or more than 100%, for example, an increase of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%. In some aspects, the modulator increases the binding of the first protein to the second protein and / or the binding of the second protein to the first protein by at least 90% (e.g., 90%-100%). In some aspects, the increase in binding is at least 50% (e.g., 50%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%), for example, as measured by surface plasmon resonance, biolayer interference, or enzyme-linked immunosorbent assay (ELISA).

[0340] Indirect interaction

[0341] In some aspects, this disclosure is characterized by a regulator of the interaction between a first protein and a second protein, wherein the protein-protein interaction is an indirect interaction, and the regulator disrupts the causal relationship between the expression, activity, and / or abundance of the first member of the protein-protein interaction and the expression, activity, and / or abundance of the second member of the protein-protein interaction. For example, in some aspects, the first protein regulates the expression of the second protein (e.g., by regulating transcription or translation), and the regulator disrupts the regulation of expression; the first protein regulates the activity of the second protein (e.g., as a component of an upstream signaling pathway), and the regulator disrupts the regulation of activity; and / or the first protein regulates the abundance of the second protein (e.g., by targeting the degradation of the second protein, e.g., by acting as a ubiquitin ligase), and the regulator disrupts the regulation of abundance.

[0342] In some respects, disruption of causality leads to changes in the downstream activity of one or both members of a protein-protein interaction relative to the downstream activity in the absence of a regulator (e.g., an increase or decrease in the amount, intensity, or duration of downstream activity).

[0343] Direct and indirect interactions

[0344] In some respects, the regulator induces an increase in the downstream activity of one or both members of the protein-protein interaction relative to the downstream activity in the absence of the regulator (e.g., an increase in the amount, intensity, or duration of the downstream activity). Downstream activity can include any biological activity that occurs as a direct or indirect result of the expression and / or activity of the members of the protein-protein interaction, such as transcriptional regulation, signal transduction, and catalysis. In some respects, the increase in downstream activity is at least 40%. In some respects, the increase is to at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% or 100%, for example, to 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%.

[0345] In some respects, the modifier causes a reduction in downstream activity relative to the downstream activity in the absence of the modifier. In some respects, the downstream activity is reduced by at least 40%. In some respects, the reduction is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% or 100% (i.e., downstream activity does not occur at a detectable level), for example, a reduction of 5% to 15%, 15% to 25%, 25% to 35%, 35% to 45%, 45% to 55%, 55% to 65%, 65% to 75%, 75% to 85%, 85% to 95%, or 95% to 100%).

[0346] B. Small molecules

[0347] In some respects, regulators or candidate regulators are small molecules. Small molecules are molecules other than binding peptides or antibodies as defined herein. Binding small molecules can be identified and chemically synthesized using known methods (see, for example, PCT Publications WO00 / 00823 and WO00 / 39585). The size of binding small molecules is typically less than about 2000 Daltons (e.g., sizes less than about 2000, 1500, 750, 500, 250, or 200 Daltons), wherein such organic small molecules can bind, preferably specifically, to the peptides described herein, and can be identified using well-known techniques without excessive experimentation. In this regard, it is noted that techniques for screening small molecule libraries for molecules capable of binding peptide targets are well-known in the art (see, for example, PCT Publications WO00 / 00823 and WO00 / 39585). Binding small molecules can be, for example, aldehydes, ketones, oximes, hydrazones, ureas, etc.

[0348] Carbazide, primary amines, secondary amines, tertiary amines, N-substituted hydrazides, acyl hydrazides, alcohols, ethers, thiols, thioethers

[0349] Disulfides, carboxylic acids, esters, amides, ureas, carbamates, carbonates, ketals, thioketals, acetals, thioacetals, aryl halides, aryl sulfonates, alkyl halides, alkyl sulfonates, aromatic compounds, heterocyclic compounds, aniline, alkenes, alkynes, diols, amino alcohols, oxazolidinyl, oxazoline, thiazoline, thiazoline, enamines, sulfonamides, epoxides, aziridines, isocyanates, sulfonyl chlorides, diazo compounds, acyl chlorides, etc.

[0350] In some respects, the binding of the first protein to the second protein is reduced in the presence of small molecules (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%).

[0351] In some respects, the binding of the first protein to the second protein is increased in the presence of small molecules (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%).

[0352] In some respects, the downstream activity of the first and / or second protein is reduced in the presence of small molecules (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%).

[0353] C. Antibody-antigen binding fragments

[0354] In some respects, the modulator or candidate modulator is an antibody or its antigen-binding fragment that binds to one or both members of a protein-protein interaction. In some respects, the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, a bisomatic antibody, a linear antibody, scFv, ScFab, a VH domain, or a VHH domain.

[0355] In some respects, the modulator is a multispecific antibody, such as a bispecific antibody. In some respects, the modulator is a bispecific or multispecific antibody that binds to multiple epitopes of one or two members of a protein-protein interaction. In some respects, the modulator is a bispecific or multispecific antibody that binds to two members of a protein-protein interaction.

[0356] In some respects, the binding of the first member of a protein-protein interaction to the second member of a protein-protein interaction is reduced in the presence of an antibody or antigen-binding fragment (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%).

[0357] In some respects, the binding of the first member to the second member is increased in the presence of the antibody or antigen-binding fragment (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%).

[0358] In some respects, the downstream activity of one or both members of a protein-protein interaction is reduced in the presence of an antibody or antigen-binding fragment (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%).

[0359] In some respects, the downstream activity of one or both members of a protein-protein interaction increases in the presence of an antibody or antigen-binding fragment (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%).

[0360] D. Peptide

[0361] In some respects, regulators or candidate regulators are peptides that bind to one or both members of a protein-protein interaction. Peptides can be naturally occurring or engineered. Peptides can bind to binding partners with an affinity equal to, lower than, or higher than that of the full-length protein. In some respects, peptides perform all the functions of the full-length protein. In other respects, peptides do not perform all the functions of the full-length protein.

[0362] In some respects, the binding of the first member of a protein-protein interaction to the second member of a protein-protein interaction is reduced in the presence of the peptide (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%).

[0363] In some respects, the binding of the first member to the second member is increased in the presence of the peptide (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%).

[0364] In some respects, the downstream activity of one or both members of a protein-protein interaction is reduced in the presence of a peptide (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%).

[0365] In some respects, the downstream activity of one or both members of a protein-protein interaction increases in the presence of a peptide (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%).

[0366] E. Simulation

[0367] In some respects, regulators or candidate regulators are mimics that bind to one or both members of a protein-protein interaction, such as molecular mimics. In some respects, mimics can perform all the functions of the mimicked polypeptide. In other respects, mimics do not perform all the functions of the mimicked polypeptide.

[0368] In some respects, the binding of the first member of a protein-protein interaction to the second member of a protein-protein interaction is reduced in the presence of a mimic (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%).

[0369] In some respects, the combination of the first member and the second member increases in the presence of the analogue (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%).

[0370] In some respects, the downstream activity of one or both members of a protein-protein interaction is reduced in the presence of a mimic (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%).

[0371] In some respects, the downstream activity of one or both members of a protein-protein interaction increases in the presence of a mimic (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%).

[0372] F.PROTAC

[0373] In some respects, regulators or candidate regulators are proteolytic targeting chimeras (PROTACs) that bind to one or both members of protein-protein interactions. PROTACs are described, for example, in Sakamoto et al., Proc Natl Acad Sci USA, 98(15):8554-8559, 2001.

[0374] In some respects, the binding of the first member of a protein-protein interaction to the second member of a protein-protein interaction is reduced in the presence of PROTAC (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%). In some respects, the combination of the first member and the second member increases in the presence of PROTAC (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%).

[0375] In some respects, the downstream activity of one or both members of a protein-protein interaction is reduced in the presence of PROTAC (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%).

[0376] In some respects, the downstream activity of one or both members of a protein-protein interaction increases in the presence of PROTAC (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%).

[0377] In some respects, the abundance of one or both members of a protein-protein interaction is reduced in the presence of PROTAC (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., by 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%).

[0378] G. Determination of the regulation of protein-protein interactions

[0379] In some aspects, the assay of protein-protein interactions assesses the binding of a first member of a protein-protein interaction to a second member of a protein-protein interaction in the presence or absence of a candidate regulator. Regulation of the interaction can be identified as an increase in the protein-protein interaction in the presence of the regulator compared to the protein-protein interaction in the absence of the regulator, for example, an increase of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 90%, 95%, 100%, or more than 100% (e.g., 5%–15%, 15%–25%, 25%–35%, 35%–45%, 45%–55%, 55%–65%, 65%–75%, 75%–85%, 85%–95%, 95%–100%, or more than 100%). Alternatively, regulation can be identified as a reduction in protein-protein interactions in the presence of a regulator compared to protein-protein interactions in the absence of the regulator, for example, a reduction of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 90%, 95%, or 100% (e.g., 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%). Assays of protein-protein interactions can be, for example, SPR assays, biological layer interference (BLI) assays, enzyme-linked immunosorbent assays (ELISA), extracellular interaction assays, or cell surface interaction assays.

[0380] Exemplary methods for identifying regulators of protein-protein interactions and agents that can regulate such interactions are described in WO 2020 / 205626, which is incorporated herein by reference in its entirety.

[0381] H. Delivery method

[0382] The compositions used in the methods described herein (e.g., PROTACs, small molecules, antibodies, antigen-binding fragments, peptides, mimics, antisense oligonucleotides, or siRNAs) can be administered by any suitable method, including, for example, intravenous, intramuscular, subcutaneous, transdermal, percutaneous, arterial, peritoneal, lesion, cranial, joint, prostate, pleural, tracheal, sheath, nasal, vaginal, rectal, topical, tumor, peritoneal, subconjunctival, cystic, mucosal, pericardial, umbilical, ocular, orbital, oral, transdermal, intravitreal (e.g., intravitreal injection), via eye drops, via inhalation, via injection, via transplantation, via infusion, via continuous infusion, via local perfusion to directly irrigate target cells, via catheter, via irrigation, in the form of emulsions or lipid compositions. The compositions used in the methods described herein can also be administered systemically or locally. The method of administration can vary depending on a variety of factors (e.g., the compound or composition to be administered and the severity of the condition, disease, or disorder to be treated). In some respects, protein-protein interaction modulators are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorally, via transplantation, by inhalation, intrathecal administration, intraventricular administration, or intranasally. Administration can be made via any suitable route, such as by injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is transient or long-term. Various dosing schedules are considered, including but not limited to single or multiple administrations at various time points, bolus administration, and pulsatile infusion.

[0383] The protein-protein interaction modulators (and any additional therapeutic agents) described herein may be formulated, administered, and applied in accordance with good medical practice. Factors to be considered in this context include the specific disease being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disease, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to the practicing physician. Modulators are not mandatory, but may optionally be formulated and / or administered concurrently with one or more agents currently used for the prevention or treatment of the disease in question. The effective amount of such other agents depends on the amount of modulator present in the formulation used, the type of disease or treatment, and other factors discussed above. These are generally used at the same dosage and route of administration as described herein, or at approximately 1% to 99% of the dosage described herein, or at any dosage and via any route determined empirically / clinically to be appropriate.

[0384] III. Methods for identifying regulators of protein-protein interactions

[0385] In some aspects, this disclosure is characterized by methods for identifying regulators of the interaction between a first member and a second member of a protein-protein interaction and methods for identifying regulators of the downstream activity of one or both members of a protein-protein interaction, wherein these methods include: (a) providing a candidate regulator (e.g., a candidate regulator described in Part II herein); (b) contacting the first member of the protein-protein interaction with the second member of the protein-protein interaction under conditions that allow the binding of the members of the protein-protein interaction, in the presence or absence of the candidate regulator; and (c) measuring the binding of the members of the protein-protein interaction.

[0386] In some aspects, the candidate regulator is provided to cells (e.g., mammalian cells), to cell culture media, to conditioned media, and / or to a purified form of the first and second members of the protein-protein interaction. In some aspects, the candidate regulator is provided at concentrations of at least 0.1 nM, 0.5 nM, 1 nM, 10 nM, 50 nM, 100 nM, 250 nM, 500 nM, 750 nM, 1 μM, 2 μM, 3 μM, 5 μM, or 10 μM. In some aspects, the candidate regulator is provided at concentrations between 0.1 nM and 10 μM. In some aspects, the candidate regulator is provided, for example, in a soluble form in solution.

[0387] In some aspects, a candidate modifier is identified as a modifier if the increase in binding is at least 70%. In some aspects, the increase in binding is at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more than 100% (e.g., an increase of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%). In some aspects, the increase in binding is at least 70%.

[0388] In some aspects, a candidate modifier is identified as a modifier if the binding reduction is at least 70%. In some aspects, the binding reduction is at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% (e.g., a binding reduction of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%). In some aspects, the binding reduction is at least 70%.

[0389] Assays of protein-protein interactions may include, for example, SPR assays, biological layer interference (BLI) assays, enzyme-linked immunosorbent assays (ELISA), extracellular interaction assays as described in WO 2020 / 205626, or cell surface interaction assays as described in WO2020 / 205626.

[0390] A. Determination of the regulation of the interaction between Fbxw11 and Nfkb1 and / or Nfkb2

[0391] In some aspects, this disclosure is characterized by a method for identifying a regulator of the interaction between an F-box and a WD repeating domain 11 (Fbxw11) and a nuclear factor κB subunit 1 (Nfkb1) or a nuclear factor κB subunit 2 (Nfkb2), the method comprising: (a) providing a candidate regulator (e.g., a candidate regulator described in Part II herein); (b) contacting Fbxw11 with Nfkb1 or Nfkb2 in the presence or absence of the candidate regulator under conditions that allow binding of Fbxw11 with Nfkb1 or Nfkb2; and (c) measuring the binding of Fbxw11 with Nfkb1 or Nfkb2, wherein an increase or decrease in binding in the presence of the candidate regulator relative to binding in the absence of the candidate regulator identifies the candidate regulator as a regulator of the interaction between Fbxw11 and Nfkb1 or Nfkb2.

[0392] In some aspects, this disclosure is characterized by a method for identifying a regulator of the downstream activity of Fbxw11, the method comprising: (a) providing a candidate regulator; (b) contacting Fbxw11 with Nfkb1 or Nfkb2 in the presence or absence of the candidate regulator under conditions that allow binding of Fbxw11 to Nfkb1 or Nfkb2; and (c) measuring the downstream activity of Fbxw11, wherein a change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of Fbxw11.

[0393] In some aspects, this disclosure is characterized by a method for identifying a regulator of the downstream activity of Nfkb1 or Nfkb2, the method comprising: (a) providing a candidate regulator; (b) contacting Nfkb1 or Nfkb2 with Fbxw11 in the presence or absence of the candidate regulator under conditions that allow binding of Nfkb1 or Nfkb2 to Fbxw11; and (c) measuring the downstream activity of Nfkb1 or Nfkb2, wherein a change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of Nfkb1 or Nfkb2.

[0394] In some respects, the increase or decrease in binding is at least 50% (e.g., 50%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%), as measured by surface plasmon resonance, biolayer interference, or enzyme-linked immunosorbent assay (ELISA).

[0395] In some respects, the modulator is an inhibitor of the downstream activity of Fbxw11, Nfkb1, or Nfkb2.

[0396] In some respects, the modulator is a modulator as described in Part II of this document, for example, a proteolytic targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment (e.g., bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, bispecific antibody, linear antibody, scFv, scFab, VH domain or VHH domain), peptide, mimic, or repressive nucleic acid (e.g., ASO or siRNA).

[0397] In some aspects, where the modulator is an antibody or its antigen-binding fragment, the antibody or its antigen-binding fragment binds to Fbxw11. In some aspects, the antibody or its antigen-binding fragment binds to Nfkb1 and / or Nfkb2. For example, in some aspects, the modulator is an antibody or its antigen-binding fragment that binds to Fbxw11, an antibody or its antigen-binding fragment that binds to Nfkb1 or Nfkb2, or an antibody or its antigen-binding fragment that binds to both Fbxw11 and Nfkb1 and / or Nfkb2.

[0398] In some respects, changes in downstream activity are reductions in the amount, intensity, or duration of downstream activity.

[0399] In some aspects, the downstream activity of Fbxw11 is the processing of Nfkb1 to generate active p50 and / or the processing of Nfkb2 to generate active p52. In some aspects, the processing of Nfkb1 to generate active p50 and / or the processing of Nfkb2 to generate active p52 is reduced in the presence of a modifier. The reduction in processing can be at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% (e.g., it can be a reduction of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%). In other respects, the processing of Nfkb1 to generate active p50 and / or the processing of Nfkb2 to generate active p52 is increased in the presence of a modifier. The increase in processing can be at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more than 100% (e.g., it can be an increase of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%).

[0400] In some aspects, the downstream activities of Fbxw11, Nfkb1, and / or Nfkb2 are immune response activation. In some aspects, immune response activation is reduced in the presence of a modulator. The reduction in activation can be at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% (e.g., a reduction of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%). In other aspects, immune response activation is increased in the presence of a modulator. The increase in activation can be at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more than 100% (e.g., it can be an increase of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%).

[0401] B. Treatment methods using modulators of the interaction between Fbxw11 and Nfkb1 and / or Nfkb2

[0402] In some respects, this disclosure is characterized by a method for preventing or treating an individual’s cancer, inflammatory disease or autoimmune disease, the method comprising administering to the individual an effective amount of a modulator identified by the method presented in Part III(A) above, thereby treating the individual.

[0403] In some aspects, this disclosure is characterized by a method for treating cancer in an individual, the method comprising administering to the individual an effective amount of a modulator of the interaction between Fbxw11 and one or both of Nfkb1 and Nfkb2, wherein activation of the immune response is increased in the presence of the modulator.

[0404] In some aspects, this disclosure is characterized by a method for treating an individual with an inflammatory disease or an autoimmune disease, the method comprising administering to the individual an effective amount of a modulator of the interaction between Fbxw11 and one or both of Nfkb1 and Nfkb2, wherein activation of the immune response is reduced in the presence of the modulator.

[0405] C. Determination of the regulation of the interaction between Rfwd2 and Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, or Wdr5

[0406] In some aspects, this disclosure is characterized by a method for identifying regulators of the interaction between the ring finger and WD repeat domain 2 (Rfwd2) and a query protein selected from Forkhead Box L2 (Foxl2), JunD, WD repeat domain 82 (Wdr82); E1A-binding protein p300 (Ep300); late-promoting complex subunit 13 (Anapc13); Cullin 2 (Cul2); Cullin 5 (Cul5); E3 ubiquitin ligase 1 (Huwe1) containing HECT, UBA, and WWE domains; CREB-binding protein (Crebbp); S-phase kinase-associated protein 1 (Skp1a); developmentally downregulated gene 8 expressed by neural progenitor cells (Nedd8); Cullin 1 (Cul1); and WD repeat domain 5 (Wdr5), the method comprising: (a) providing a candidate regulator (e.g., a candidate regulator described in Part II of this document); (b) contacting Rfwd2 with a query protein in the presence or absence of the candidate regulator under conditions that allow Rfwd2 to bind to the query protein; and (c) measuring the binding of Rfwd2 to the query protein, wherein an increase or decrease in binding in the presence of the candidate regulator relative to binding in the absence of the candidate regulator identifies the candidate regulator as a regulator of the interaction between Rfwd2 and the query protein.

[0407] In some aspects, this disclosure is characterized by a method for identifying regulators of downstream activity of Rfwd2, the method comprising: (a) providing a candidate regulator; (b) contacting Rfwd2 with a query protein selected from Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5 in the presence or absence of the candidate regulator, under conditions allowing the query protein selected from Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5 to bind to the query protein; and (c) measuring the downstream activity of Rfwd2, wherein the change in downstream activity in the presence of the candidate regulator relative to the change in downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of downstream activity of Rfwd2.

[0408] In some aspects, this disclosure is characterized by a method for identifying a regulator of the downstream activity of a query protein selected from Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5, the method comprising: (a) providing a candidate regulator; (b) contacting the query protein with Rfwd2 in the presence or absence of the candidate regulator under conditions that allow the query protein to bind to Rfwd2; and (c) measuring the downstream activity of the query protein, wherein a change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of the query protein.

[0409] In some respects, the increase or decrease in binding is at least 50% (e.g., 50%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%), as measured by surface plasmon resonance, biolayer interference, or enzyme-linked immunosorbent assay (ELISA).

[0410] In some respects, the regulator is an inhibitor of the downstream activity of Rfwd2 or the query protein.

[0411] In some respects, the modulator is a modulator as described in Part II of this document, for example, a proteolytic targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment (e.g., bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, bispecific antibody, linear antibody, scFv, scFab, VH domain or VHH domain), peptide, mimic, or repressive nucleic acid (e.g., ASO or siRNA).

[0412] In some aspects, the modulator is an antibody or its antigen-binding fragment, which binds to Rfwd2. In other aspects, the antibody or its antigen-binding fragment binds to the query protein. For example, in some aspects, the modulator is an antibody or its antigen-binding fragment that binds to Rfwd2, an antibody or its antigen-binding fragment that binds to the query protein, or an antibody or its antigen-binding fragment that binds to both Rfwd2 and the query protein.

[0413] In some respects, changes in downstream activity are reductions in the amount, intensity, or duration of downstream activity.

[0414] In some respects, the downstream activities of Fbxw11, Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and / or Wdr5 promote dendritic cell and / or macrophage migration. In other respects, dendritic cell and / or macrophage migration is reduced in the presence of modulators. The reduction in dendritic cell and / or macrophage migration can be at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% (e.g., a reduction of 5%–15%, 15%–25%, 25%–35%, 35%–45%, 45%–55%, 55%–65%, 65%–75%, 75%–85%, 85%–95%, or 95%–100%). In other respects, dendritic cell and / or macrophage migration is increased in the presence of the modulator. The increase in dendritic cell and / or macrophage migration can be at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more than 100% (e.g., it can be an increase of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100%).

[0415] D. Treatment methods using modulators of the interaction between Rfwd2 and Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, or Wdr5.

[0416] In some respects, this disclosure is characterized by a method for preventing or treating an individual’s cancer, inflammatory disease, or autoimmune disease, the method comprising administering to the individual an effective amount of a modulator identified by the method presented in Part III(C) above, thereby treating the individual.

[0417] In some aspects, this disclosure is characterized by a method for treating an individual with an inflammatory disease or an autoimmune disease, the method comprising administering to the individual an effective amount of a modulator of the interaction between Rfwd2 and one or more of Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1 and Wdr5, wherein dendritic cell or macrophage migration is reduced in the presence of the modulator.

[0418] In some respects, this disclosure is characterized by a method for treating cancer in an individual, the method comprising administering to the individual an effective amount of a modulator of the interaction between Rfwd2 and one or more of Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1 and Wdr5, wherein dendritic cell or macrophage migration is increased in the presence of the modulator.

[0419] E. Determination of the regulation of the interaction between the protein complex containing Ptpn11 and Rfwd2 and Cebp family transcription factors

[0420] In some aspects, this disclosure is characterized by a method for identifying regulators of interactions between a protein complex and a CCAAT enhancer-binding protein (Cebp) family transcription factor, the protein complex comprising a non-receptor tyrosine protein phosphatase 11 (Ptpn11) and a ring finger and WD repeat domain 2 (Rfwd2), the method comprising: (a) providing a candidate regulator (e.g., a candidate regulator described in Part II herein); (b) contacting the protein complex with a Cebp family transcription factor in the presence or absence of the candidate regulator under conditions that allow binding of the protein complex to the Cebp family transcription factor; and (c) measuring the binding of the protein complex to the Cebp family transcription factor, wherein an increase or decrease in binding in the presence of the candidate regulator relative to binding in the absence of the candidate regulator identifies the candidate regulator as a regulator of the interaction between the protein complex and the Cebp family transcription factor.

[0421] In some aspects, this disclosure is characterized by a method for identifying regulators of the downstream activity of a protein complex comprising Ptpn11 and Rfwd2, the method comprising: (a) providing a candidate regulator; (b) contacting the protein complex with a Cebp family transcription factor in the presence or absence of the candidate regulator under conditions allowing the protein complex to bind to the Cebp family transcription factor; and (c) measuring the downstream activity of the protein complex, wherein a change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of the protein complex.

[0422] In some aspects, this disclosure is characterized by a method for identifying regulators of Cebp family transcription factors, the method comprising: (a) providing a candidate regulator; (b) contacting a Cebp family transcription factor with a protein complex comprising Ptpn11 and Rfwd2 in the presence or absence of the candidate regulator under conditions allowing binding of the Cebp family transcription factor to the protein complex; and (c) measuring the downstream activity of the query protein, wherein a change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of the query protein.

[0423] In some respects, the increase or decrease in binding is at least 50% (e.g., 50%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%), as measured by surface plasmon resonance, biolayer interference, or enzyme-linked immunosorbent assay (ELISA).

[0424] In some respects, the regulator is an inhibitor of the downstream activity of Cebp family transcription factors and / or protein complexes containing Ptpn11 and Rfwd2.

[0425] In some respects, the modulator is a modulator as described in Part II of this document, for example, a proteolytic targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment (e.g., bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, bispecific antibody, linear antibody, scFv, scFab, VH domain or VHH domain), peptide, mimic, or repressive nucleic acid (e.g., ASO or siRNA).

[0426] In some aspects, the regulator is an antibody or its antigen-binding fragment, which binds to one or both of Ptpn11 and Rfwd2. In some aspects, the antibody or its antigen-binding fragment binds to Cebp family transcription factors. For example, in some aspects, the regulator is an antibody or its antigen-binding fragment that binds to Fbxw11, an antibody or its antigen-binding fragment that binds to one, two, or all three of Ptpn11, Rfwd2, and Cebp family transcription factors, or an antibody or its antigen-binding fragment that binds to Cebp family transcription factors and one or both of Ptpn11 and Rfwd2. IV. Methods for the prevention or treatment of diseases or disorders associated with APC.

[0427] In some aspects, this disclosure features a method for preventing or treating an individual's disease or ailment related to antigen-presenting cells (APCs) and / or inflammation, the method comprising administering to the individual an effective amount of a regulator of a gene from Table 1 or Table 2, thereby treating the individual. Therefore, in some aspects, this disclosure features a method for preventing or treating an individual's disease or ailment related to APCs and / or inflammation, the method comprising administering to the individual an effective amount of a regulator of a gene from Table 1, thereby treating the individual. In some aspects, this disclosure features a method for preventing or treating an individual's disease or ailment related to APCs and / or inflammation, the method comprising administering to the individual an effective amount of a regulator of a gene from Table 2, thereby treating the individual.

[0428] Table 1. Members of cofunctional gene modules that have no known role in dendritic cells or inflammation.

[0429]

[0430]

[0431]

[0432] Table 2. Members of cofunctional gene modules that have no known role in dendritic cells or inflammation.

[0433]

[0434]

[0435]

[0436] In some respects, regulators regulate the expression of genes listed in Table 1 or Table 2. In other respects, regulators regulate the expression or activity of proteins encoded by genes listed in Table 1 or Table 2.

[0437] In some respects, regulators regulate the abundance of proteins encoded by the genes in Table 1 or Table 2, for example, by regulating protein degradation.

[0438] In some respects, the regulators cause changes in the downstream activity of proteins encoded by the genes in Table 1 or Table 2 in the presence of the regulators relative to the downstream activity in the absence of the regulators.

[0439] In some aspects, the regulator is an activator of the downstream activity of the genes in Table 1 or Table 2. In some aspects, the regulator causes an increase in the downstream activity of the protein encoded by the gene in Table 1 or Table 2 relative to the downstream activity in the absence of the regulator (e.g., an increase in the amount, intensity, or duration of the downstream activity). Downstream activity can include any biological activity that occurs as a direct or indirect result of the expression and / or activity of the protein encoded by the gene in Table 1 or Table 2 in, for example, transcriptional regulation, signal transduction, and catalysis. In some aspects, the downstream activity is increased by at least 40%. In some respects, the increase is to at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% or 100%, for example, to 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100%.

[0440] In some respects, the regulator is an inhibitor of the downstream activity of the genes listed in Table 1 or Table 2. In some respects, the regulator causes a reduction in the downstream activity of the proteins encoded by the genes listed in Table 1 or Table 2 relative to the downstream activity in the absence of the regulator. In some respects, the reduction in downstream activity is at least 40%. In some respects, the reduction is to at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% or 100% (i.e., downstream activity does not occur at a detectable level), for example, to 5% to 15%, 15% to 25%, 25% to 35%, 35% to 45%, 45% to 55%, 55% to 65%, 65% to 75%, 75% to 85%, 85% to 95%, or 95% to 100%).

[0441] In some respects, the modulator is a modulator as described in Part II of this document, for example, a proteolytic targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment (e.g., bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, bispecific antibody, linear antibody, scFv, scFab, VH domain or VHH domain), peptide, mimic, or repressive nucleic acid (e.g., ASO or siRNA).

[0442] In some aspects, the regulator is an antibody or its antigen-binding fragment, which binds to proteins encoded by genes listed in Table 1 or Table 2.

[0443] In some respects, an individual's disease or condition associated with APC and / or inflammation is a disease or condition associated with dendritic cells (DCs), macrophages, glial cells, or B cells. For example, APC may be DCs, macrophages, glial cells (e.g., microglia, astrocytes, or oligodendrocytes), or B cells. In some respects, APC may be DCs.

[0444] In some respects, diseases or disorders associated with APC and / or inflammation include neurodegenerative diseases (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD)), arthritis, allergic reactions, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or blastic plasmacytoid dendritic cell tumors. In other respects, diseases or disorders associated with APC and / or inflammation include encephalitis, myelitis, meningitis, arachnoiditis, neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, and otitis externa.

[0445] Otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillary inflammation, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleurisy, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, salivary gland inflammation / parotitis, cheilitis, pulpitis, jaw inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, cecal inflammation, appendicitis, proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis. Arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, origin-endocrine inflammation, fasciitis, bursitis, epicondylitis, tendinitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, posthitis, balanoposthitis, chorioamnionitis, omphalitis, pancreatitis, pituitary inflammation, thyroiditis, parathyroiditis, adrenalitis, lymphangitis or lymphadenitis.

[0446] In some respects, the gene in Table 1 or Table 2 is Vhl or Huwe1, and the regulator is a PROTAC that functions as an E3 ligase together with Vhl, for example, the PROTAC provided in Wang et al., Eur. J. Med. Chem., Jan 5; 227:113906, 2022. In some respects, the gene in Table 1 or Table 2 is Huwe1, and the regulator is the agent provided in Crawford et al., Oncogene, 39(27):5001-5014, 2020.

[0447] In some aspects, this disclosure is characterized by a method for monitoring the response of an individual suffering from a disease or disorder associated with APC and / or inflammation to treatment with a modulator of the genes in Table 1 or Table 2, the method comprising: (a) determining the expression level of the genes in Table 1 or Table 2 in a biological sample obtained from the individual at a time point following administration of the modulator; and (b) comparing the expression level of the genes in Table 1 or Table 2 in the biological sample with a reference level, thereby monitoring the individual's response to treatment with the modulator.

[0448] In some aspects, this disclosure is characterized by a method for monitoring the response of an individual suffering from a disease or disorder associated with APC and / or inflammation to treatment with a modulator of the genes in Table 1, the method comprising: (a) determining the expression level of the genes in Table 1 in a biological sample obtained from the individual at a time point following administration of the modulator; and (b) comparing the expression level of the genes in Table 1 in the biological sample with a reference level, thereby monitoring the individual's response to treatment with the modulator.

[0449] In some aspects, this disclosure is characterized by a method for monitoring the response of an individual suffering from a disease or disorder associated with APC and / or inflammation to treatment with a modulator of the genes in Table 2, the method comprising: (a) determining the expression level of the genes in Table 2 in a biological sample obtained from the individual at a time point following administration of the modulator; and (b) comparing the expression level of the genes in Table 2 in the biological sample with a reference level, thereby monitoring the individual's response to treatment with the modulator.

[0450] In some respects, the reference level is selected from the group consisting of: (i) gene expression levels in biological samples obtained from individuals prior to the application of the regulator; (ii) gene expression levels in a reference population; (iii) pre-specified expression levels for the gene; or (iv) gene expression levels in biological samples obtained from individuals at a previous time point, wherein the previous time point is after the application of the regulator.

[0451] In some respects, the expression levels of genes in Table 1 or Table 2 in biological samples obtained from the individual are reduced relative to reference levels, and the method further includes administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that increases the expression and / or activity of genes in Table 1 or Table 2.

[0452] In some respects, the expression levels of genes in Table 1 or Table 2 in biological samples obtained from the individual are increased relative to reference levels, and the method further includes administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that reduces the expression and / or activity of genes in Table 1 or Table 2.

[0453] V. Methods for targeting CCR7 and its interacting mates

[0454] A. Treatment methods

[0455] In some respects, this disclosure is characterized by a method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering to the individual an effective amount of one, two, or all three of (a) LIM domain-binding protein 2 (Ldb2), ring finger protein 165 (Rnf165), and TNF receptor-associated factor 2 (Traf2) as a modulator of the interaction between (b) chemokine receptor type 7 (CCR7).

[0456] In some aspects, the modulator is a modulator as described in Part II of this document, for example, a proteolytic targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment (e.g., bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, bispecific antibody, linear antibody, scFv, scFab, VH domain or VHH domain) (e.g., an antibody or its antigen-binding fragment that binds to one, two or all three of Ldb2, Rnf165 and Traf2 and / or binds to CCR7), a peptide, a mimic, or an inhibitory nucleic acid (e.g., ASO or siRNA). In some aspects, the modulator is a bispecific antibody comprising an antigen-binding domain targeting the tumor microenvironment (e.g., a bispecific antibody comprising a first binding domain that binds to one, two or all three of Ldb2, Rnf165 and Traf2 and / or binds to CCR7 and a second binding domain targeting the tumor microenvironment).

[0457] In some respects, the individual has cancer, and the modulator is an agent that reduces the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0458] In some cases, the individual has an inflammatory or autoimmune disease, and the modulator is an agent that increases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2. In other cases, the individual has cancer, and the modulator is an agent that increases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0459] In some respects, inflammatory or autoimmune diseases are neurodegenerative diseases (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD)), arthritis, allergies, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some respects, inflammatory or autoimmune diseases are Crohn's disease. In some respects, inflammatory or autoimmune diseases include encephalitis, myelitis, meningitis, arachnoiditis, neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillary inflammation, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleurisy, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, salivary gland inflammation / parotitis, cheilitis, pulpitis, jaw inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, cecal inflammation, and appendicitis. Proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, origin-endocrine inflammation, fasciitis, bursitis, epicondylitis, tendinitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, posthitis, balanoposthitis, chorioamnionitis, omphalitis, pancreatitis, pituitary inflammation, thyroiditis, parathyroiditis, adrenalitis, lymphangitis or lymphadenitis.

[0460] B. Methods to increase CCR7 expression

[0461] In some respects, this disclosure is characterized by a method for increasing the expression of CCR7 in antigen-presenting cells (APCs), the method comprising contacting the APCs with an effective amount of an agent that reduces the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0462] Agents that reduce the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2 can be, for example, proteolytic targeting chimeras (PROTACs) (e.g., PROTACs that direct the proteolysis of one, two, or all three of Ldb2, Rnf165, and Traf2); small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bimeric antibodies, linear antibodies, scFv, scFab, VH domains, or VHH domains) (e.g., antibodies or antigen-binding fragments thereof that bind to one, two, or all three of Ldb2, Rnf165, and Traf2 and / or bind to CCR7); peptides; mimics; or repressive nucleic acids (e.g., ASO or siRNA). In some respects, the agent is a bispecific antibody containing an antigen-binding domain that targets the tumor microenvironment (e.g., a bispecific antibody containing a first binding domain that binds to one, two, or all three of Ldb2, Rnf165, and Traf2 and / or binds to CCR7 and a second binding domain that targets the tumor microenvironment).

[0463] In some aspects, CCR7 expression in APCs is increased by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more than 100% relative to expression in the absence of the drug (e.g., an increase of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100% relative to expression in the absence of the drug). In some aspects, CCR7 expression in APCs is increased by at least 10% relative to expression in the absence of the drug.

[0464] In some respects, APCs are dendritic cells (DCs), macrophages, glial cells (e.g., microglia, astrocytes, or oligodendrocytes), or B cells. In other respects, APCs are DCs.

[0465] In some respects, APC exists within an individual. In some respects, the individual has cancer.

[0466] C. Methods to increase the migration of APCs to tumors and / or lymph nodes

[0467] In some aspects, this disclosure is characterized by a method for increasing the migration of APCs to tumors and / or one or more lymph nodes in an individual (e.g., an individual with cancer), the method comprising administering to the individual an effective amount of an agent that reduces the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0468] Agents that reduce the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2 can be, for example, proteolytic targeting chimeras (PROTACs) (e.g., PROTACs that direct the proteolysis of one, two, or all three of Ldb2, Rnf165, and Traf2); small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bimeric antibodies, linear antibodies, scFv, scFab, VH domains, or VHH domains) (e.g., antibodies or antigen-binding fragments thereof that bind to one, two, or all three of Ldb2, Rnf165, and Traf2 and / or bind to CCR7); peptides; mimics; or repressive nucleic acids (e.g., ASO or siRNA). In some respects, the agent is a bispecific antibody containing an antigen-binding domain that targets the tumor microenvironment (e.g., a bispecific antibody containing a first binding domain that binds to one, two, or all three of Ldb2, Rnf165, and Traf2 and / or binds to CCR7 and a second binding domain that targets the tumor microenvironment).

[0469] In some respects, the individual has cancer, and the migration of APCs to the tumor site in the individual is increased by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more than 100% relative to migration in the absence of the drug (e.g., an increase of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100% relative to migration in the absence of the drug). In some respects, the migration of APCs to the tumor site in the individual is increased by at least 10% relative to migration in the absence of the drug.

[0470] In some respects, the migration of APCs to one or more lymph nodes in an individual is at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more than 100% greater than the migration in the absence of the drug (e.g., an increase of 5%–15%, 15%–25%, 25%–35%, 35%–45%, 45%–55%, 55%–65%, 65%–75%, 75%–85%, 85%–95%, 95%–100%, or more than 100% greater than the migration in the absence of the drug). In some respects, the migration of APCs to one or more lymph nodes in an individual is at least 10% greater than the migration in the absence of the drug.

[0471] In some respects, APCs are dendritic cells (DCs), macrophages, glial cells (e.g., microglia, astrocytes, or oligodendrocytes), or B cells. In other respects, APCs are dendritic cells (DCs).

[0472] In some respects, the individual has cancer.

[0473] D. Methods to increase T cell homing to tumors

[0474] In some aspects, this disclosure is characterized by a method for increasing T cell homing to a tumor in an individual (e.g., an individual with cancer), the method comprising administering to the individual an effective amount of an agent that reduces the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2, wherein the agent increases the migration of dendritic cells in the individual to the tumor.

[0475] Agents that reduce the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2 can be, for example, proteolytic targeting chimeras (PROTACs) (e.g., PROTACs that direct the proteolysis of one, two, or all three of Ldb2, Rnf165, and Traf2); small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bimeric antibodies, linear antibodies, scFv, scFab, VH domains, or VHH domains) (e.g., antibodies or antigen-binding fragments thereof that bind to one, two, or all three of Ldb2, Rnf165, and Traf2 and / or bind to CCR7); peptides; mimics; or repressive nucleic acids (e.g., ASO or siRNA). In some respects, the agent is a bispecific antibody containing an antigen-binding domain that targets the tumor microenvironment (e.g., a bispecific antibody containing a first binding domain that binds to one, two, or all three of Ldb2, Rnf165, and Traf2 and / or binds to CCR7 and a second binding domain that targets the tumor microenvironment).

[0476] In some respects, T cell homing to the tumor in an individual is increased by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more than 100% relative to T cell homing in the absence of the drug (e.g., an increase of 5%–15%, 15%–25%, 25%–35%, 35%–45%, 45%–55%, 55%–65%, 65%–75%, 75%–85%, 85%–95%, 95%–100%, or more than 100% relative to T cell homing in the absence of the drug). In some respects, T cell homing to the tumor in the individual is increased by at least 10% relative to T cell homing in the absence of the drug.

[0477] E. Combination therapy

[0478] Any method in Parts V(A) through V(D) may further include administering one or more additional agents to an individual or exposing the APC to one or more additional agents (e.g., administering one or more additional agents before, during or after treatment with a modulator of the interaction between (a) Ldb2, Rnf165 and Traf2, two or all of them and (b) CCR7, or an agent that reduces the expression and / or activity of one, two or all of Ldb2, Rnf165 and Traf2).

[0479] In some respects, additional agents are agents that regulate the expression of one or more members of module M3 as presented in Example 3, such as those regulating Akt1, Ankfy1, Apc, Arpc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbxl13, Fbxo28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, Mlst 8. Expressions of one or more of the following: Mtor, Nosip, Paf1, Pik3r4, Pparg, Ppp2r2a, Ppp2r2d, Preb, Rbbp4, Rbbp5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13, Sec31a, Smad2, Syvn1, Taf5l, Traf2, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1, and Zbtb11.

[0480] F. Cell therapy with alterations to CCR7 or its interactants

[0481] In some respects, this disclosure is characterized by a method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering to the individual an effective amount of a cell therapy (e.g., a cell therapy as described in Part VIII of this document), which includes loss-of-function alterations of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0482] In some respects, this disclosure provides a genetically modified isolated cell containing loss-of-function alterations of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0483] In some respects, loss-of-function alterations are loss-of-function mutations (e.g., mutations that result in reduced or eliminated protein function, including deletions). In other respects, loss-of-function alterations are knockout (KO) mutations.

[0484] In some respects, this disclosure is characterized by a method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering to the individual an effective amount of a cell therapy comprising gain-of-function alterations to CCR7.

[0485] In some respects, this disclosure provides a genetically modified isolated cell containing gain-of-function alterations to CCR7.

[0486] In some respects, gain-of-function alterations are gain-of-function mutations (e.g., mutations that lead to increased gene function, including overexpression and gene duplication). In other respects, gain-of-function alterations are overexpression.

[0487] In some respects, the genetically modified isolated cells are dendritic cells, macrophages, T cells, TILs, or NK cells.

[0488] In some respects, cell therapy includes dendritic cell therapy, macrophage therapy, ACT, TIL therapy, engineered TCR therapy, CAR-T therapy, CAR-Treg therapy, or NK cell therapy.

[0489] G. Methods for monitoring response to treatment

[0490] In another aspect, this disclosure is characterized by a method for monitoring the response of an individual suffering from cancer, an inflammatory disease, or an autoimmune disease to treatment with a modulator of the interaction between (a) one, two, or all three of Ldb2, Rnf165, and Traf2 and (b) CCR7, the method comprising: (i) determining the expression levels of one or more of Ldb2, Rnf165, and Traf2 in a biological sample obtained from the individual at a time point following administration of the modulator; and (ii) comparing the expression levels of one or more genes in the biological sample to a reference level, thereby monitoring the individual's response to treatment with the modulator.

[0491] In some respects, the reference level is selected from the group consisting of: (i) the expression level of one or more genes in a biological sample obtained from an individual prior to the administration of the regulator; (ii) the expression level of one or more genes in a reference population; (iii) a pre-specified expression level for one or more genes; or (iv) the expression level of one or more genes in a biological sample obtained from an individual at a previous time point, wherein the previous time point is after the administration of the regulator.

[0492] In some respects, the individual has cancer, the expression levels of one or more genes in a biological sample obtained from the individual are increased relative to a reference level, and the method further includes administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that reduces the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0493] In some respects, the individual suffers from an inflammatory disease or an autoimmune disease, the expression levels of one or more genes in a biological sample obtained from the individual are reduced relative to a reference level, and the method further includes administering one or more additional doses of the modulator to the individual; wherein the modulator is an agent that increases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0494] VI. Methods for regulating migrating dendritic cells

[0495] A. Methods for treating cancer, inflammatory diseases, or autoimmune diseases

[0496] In some aspects, this disclosure is characterized by a method for treating an individual with cancer, inflammatory disease, autoimmune disease, or infectious disease (e.g., an infectious disease that would benefit from an enhanced immune response), the method comprising administering to the individual an effective amount of: (a) an agent that reduces the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) an agent that reduces the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) an agent that increases the expression and / or activity of death-inducing termination factor 1 (Dido1).

[0497] Agents that reduce the expression and / or activity of Cebpb, reduce the expression and / or activity of Traf2, or increase the expression and / or activity of Dido1 can be, for example, proteolytic targeting chimeras (PROTAC); small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bimeric antibodies, linear antibodies, scFv, scFab, VH domains, or VHH domains) (e.g., antibodies or antigen-binding fragments thereof that bind to Cebpb, Traf2, and / or Dido1); peptides; mimics; or repressive nucleic acids (e.g., ASO or siRNA).

[0498] In another aspect, this disclosure is characterized by a method for treating an individual with an inflammatory disease, an autoimmune disease, or an infectious disease (e.g., an infectious disease accompanied by an excessive immune response), the method comprising administering to the individual an effective amount of: (a) an agent that increases the expression and / or activity of Cebpb; (b) an agent that increases the expression and / or activity of Traf2; and / or (c) an agent that decreases the expression and / or activity of Dido1.

[0499] Agents that increase the expression and / or activity of Cebpb, increase the expression and / or activity of Traf2, or decrease the expression and / or activity of Dido1 can be, for example, PROTACs; small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bimeric antibodies, linear antibodies, scFv, scFab, VH domains, or VHH domains) (e.g., antibodies or antigen-binding fragments thereof that bind to Cebpb, Traf2, and / or Dido1); peptides; mimics; or inhibitory nucleic acids (e.g., ASO or siRNA).

[0500] In some respects, inflammatory or autoimmune diseases are neurodegenerative diseases (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD)), arthritis, allergies, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some respects, inflammatory or autoimmune diseases are Crohn's disease. In some respects, inflammatory or autoimmune diseases include encephalitis, myelitis, meningitis, arachnoiditis, neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillary inflammation, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleurisy, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, salivary gland inflammation / parotitis, cheilitis, pulpitis, jaw inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, cecal inflammation, and appendicitis. Proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, origin-endocrine inflammation, fasciitis, bursitis, epicondylitis, tendinitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, posthitis, balanoposthitis, chorioamnionitis, omphalitis, pancreatitis, pituitary inflammation, thyroiditis, parathyroiditis, adrenalitis, lymphangitis or lymphadenitis.

[0501] In some respects, autoimmune diseases are associated with a reduced proportion of migratory dendritic cells (mDCs). In other respects, individuals have loss-of-function mutations in Dido1.

[0502] B. Methods to increase the proportion of MDC

[0503] In another aspect, this disclosure is characterized by a method for increasing the proportion of migratory dendritic cells (mDCs) in an individual (e.g., an individual with cancer, an inflammatory disease, or an autoimmune disease), the method comprising administering to the individual an effective amount of: (a) an agent that reduces the expression and / or activity of Cebpb; (b) an agent that reduces the expression and / or activity of Traf2; and / or (c) an agent that increases the expression and / or activity of death-inducing termination factor 1 (Dido1).

[0504] Agents that reduce the expression and / or activity of Cebpb, reduce the expression and / or activity of Traf2, or increase the expression and / or activity of Dido1 can be, for example, PROTACs; small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bimeric antibodies, linear antibodies, scFv, scFab, VH domains, or VHH domains) (e.g., antibodies or antigen-binding fragments thereof that bind to Cebpb, Traf2, and / or Dido1); peptides; mimics; or inhibitory nucleic acids (e.g., ASO or siRNA).

[0505] In some respects, the proportion of mDC in an individual is the proportion in the individual's tumor or tissue.

[0506] In some aspects, the proportion of mDCs in an individual (e.g., in the individual's tumor or tissue) increases by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more than 100% relative to the proportion of mDCs in the absence of the drug (e.g., an increase of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100% relative to the proportion of mDCs in the absence of the drug). In some aspects, the proportion of mDCs in an individual (e.g., in the individual's tumor or tissue) increases by at least 10% relative to the proportion in the absence of the drug.

[0507] C. Methods to increase anti-tumor immunity

[0508] In another aspect, this disclosure is characterized by a method for increasing the antitumor immunity of an individual (e.g., an individual with cancer), the method comprising administering to the individual an effective amount of: (a) an agent that reduces the expression and / or activity of Cebpb; (b) an agent that reduces the expression and / or activity of Traf2; and / or (c) an agent that increases the expression and / or activity of Dido1.

[0509] Agents that reduce the expression and / or activity of Cebpb, reduce the expression and / or activity of Traf2, or increase the expression and / or activity of Dido1 can be, for example, PROTACs; small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bimeric antibodies, linear antibodies, scFv, scFab, VH domains, or VHH domains) (e.g., antibodies or antigen-binding fragments thereof that bind to Cebpb, Traf2, and / or Dido1); peptides; mimics; or inhibitory nucleic acids (e.g., ASO or siRNA).

[0510] In some aspects, the antitumor immunity in an individual (e.g., in the individual's tumor or tissue) is increased by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more than 100% relative to the antitumor immunity in the absence of the drug (e.g., an increase of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100% relative to the antitumor immunity in the absence of the drug). In some aspects, the antitumor immunity in an individual (e.g., in the individual's tumor or tissue) is increased by at least 10% relative to the antitumor immunity in the absence of the drug.

[0511] D. Methods to reduce the proportion of MDC

[0512] In another aspect, this disclosure is characterized by a method for reducing the proportion of mDCs in an individual (e.g., an individual suffering from an inflammatory disease or an autoimmune disease), the method comprising administering to the individual an effective amount of: (a) an agent that increases the expression and / or activity of Cebpb; (b) an agent that increases the expression and / or activity of Traf2; and / or (c) an agent that decreases the expression and / or activity of Dido1.

[0513] Agents that increase the expression and / or activity of Cebpb, increase the expression and / or activity of Traf2, or decrease the expression and / or activity of Dido1 can be, for example, PROTACs; small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bimeric antibodies, linear antibodies, scFv, scFab, VH domains, or VHH domains) (e.g., antibodies or antigen-binding fragments thereof that bind to Cebpb, Traf2, and / or Dido1); peptides; mimics; or inhibitory nucleic acids (e.g., ASO or siRNA).

[0514] In some respects, the proportion of mDC in an individual is the proportion in the individual's tumor or tissue.

[0515] In some aspects, the proportion of mDCs in an individual (e.g., in the tissues of an individual affected by an inflammatory disease or autoimmune disease) is reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% relative to the proportion of mDCs in the absence of the drug (e.g., a reduction of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100% relative to the proportion of mDCs in the absence of the drug). In some aspects, the proportion of mDCs in an individual (e.g., in the individual's tumor or tissues) is reduced by at least 10% relative to the proportion in the absence of the drug.

[0516] E. Methods for reducing autoimmune activity (by reducing the fraction of mDC)

[0517] In another aspect, this disclosure is characterized by a method for reducing the autoimmune activity of an individual (e.g., an individual with an autoimmune disease), the method comprising administering to the individual an effective amount of: (a) an agent that increases the expression and / or activity of Cebpb; (b) an agent that increases the expression and / or activity of Traf2; and / or (c) an agent that decreases the expression and / or activity of Dido1.

[0518] Agents that increase the expression and / or activity of Cebpb, increase the expression and / or activity of Traf2, or decrease the expression and / or activity of Dido1 can be, for example, PROTACs; small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bimeric antibodies, linear antibodies, scFv, scFab, VH domains, or VHH domains) (e.g., antibodies or antigen-binding fragments thereof that bind to Cebpb, Traf2, and / or Dido1); peptides; mimics; or inhibitory nucleic acids (e.g., ASO or siRNA).

[0519] In some aspects, the autoimmune activity in an individual (e.g., in the tissues of an individual affected by an autoimmune disease) is reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% relative to the autoimmune activity in the absence of the drug (e.g., a reduction of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or 100% relative to the autoimmune activity in the absence of the drug). In some aspects, the autoimmune activity in an individual (e.g., in the tumor or tissues of an individual) is reduced by at least 10% relative to the autoimmune activity in the absence of the drug.

[0520] F. Combination therapy

[0521] Any method in Parts VI(A) through VI(E) may further include administering one or more additional agents to the individual (e.g., administering one or more additional agents before, during, or after treatment with an agent that reduces the expression and / or activity of Cebpb; an agent that reduces the expression and / or activity of Traf2; an agent that increases the expression and / or activity of Dido1; an agent that increases the expression and / or activity of Cebpb; an agent that increases the expression and / or activity of Traf2; or an agent that reduces the expression and / or activity of Dido1).

[0522] In some respects, additional agents are agents that regulate the expression of one or more members of module M2 as presented in Example 3, such as those regulating Ago2, Ahr, Anapc13, Bach1, Baz1a, Bid, Bptf, Brca1, Brwd3, Btbd1, Cblc, Ccnf, Cdc27, Cntn4, Copa, Copb2, Coro1a, Cpne9, Cul4. b. Ddb1, E4f1, Ecel1, Fbxl14, Fbxl5, Fbxo11, Fbxo42, Fzr1, Gemin5, Gm10697, Gm9117, Gtf2 h2, Gtf3c1, Hdac4, Hectd1, Ift122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23, Klhl 3. Kmt2b, LOC100861784, Lrr1, Lrrc41, Map3k7, Mdm4, Mib1, Mkrn1, Mnat1, Naca, Nsmaf, Ogt , Pa2g4, Pcif1, Ppp1r11, Prc1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah2, Taf3, Expressions of one or more of the following: Tdpoz2, Tmem183a, Tnfsf11, Tradd, Traf3ip2, Trim35, Trim7, Tssc1, Ttc3, Ube2n, Ufl1, Unkl, Upf1, Vdr, Wdhd1, Wdr48, Wdr95, Wwp1, Ybx1, Zbtb14, Zbtb49, Zbtb7a, and Zmiz1.

[0523] In some respects, additional agents are agents that regulate the expression of one or more members of module M3 as presented in Example 3, such as those regulating Akt1, Ankfy1, Apc, Arpc1b, Birc2, Bmi1, Bub3, Cacybp, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbxl13, Fbxo28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, Mlst 8. Expressions of one or more of the following: Mtor, Nosip, Paf1, Pik3r4, Pparg, Ppp2r2a, Ppp2r2d, Preb, Rbbp4, Rbbp5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13, Sec31a, Smad2, Syvn1, Taf5l, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1, and Zbtb11.

[0524] G. Methods for monitoring response to treatment

[0525] In another aspect, this disclosure is characterized by a method for monitoring the response of an individual suffering from cancer, inflammatory disease, autoimmune disease, or infectious disease to treatment with an agent that (a) reduces the expression and / or activity of Cebpb; (b) reduces the expression and / or activity of Traf2; and / or (c) increases the expression and / or activity of Dido1, the method comprising: (i) determining the expression levels of one or more of Cebpb, Traf2, and Dido1 in a biological sample obtained from the individual at a time point following administration of the agent; and (ii) comparing the expression levels of one or more genes in the biological sample with reference levels, thereby monitoring the individual's response to treatment with the agent.

[0526] In another aspect, this disclosure is characterized by a method for monitoring the response of an individual suffering from an inflammatory disease, an autoimmune disease, or an infectious disease to treatment with an agent that (a) increases the expression and / or activity of Cebpb; (b) increases the expression and / or activity of Traf2; and / or (c) decreases the expression and / or activity of Dido1, the method comprising: (i) determining the expression levels of one or more of Cebpb, Traf2, and Dido1 in a biological sample obtained from the individual at a time point following administration of the agent; and (ii) comparing the expression levels of one or more genes in the biological sample with reference levels, thereby monitoring the individual's response to treatment with the agent.

[0527] In some respects, the reference level is selected from the group consisting of: (i) the expression level of one or more genes in a biological sample obtained from an individual prior to drug administration; (ii) the expression level of one or more genes in a reference population; (iii) a pre-specified expression level for one or more genes; or (iv) the expression level of one or more genes in a biological sample obtained from an individual at a previous time point, wherein the previous time point is after drug administration.

[0528] In some aspects, (a) the expression and / or activity of Cebpb in a biological sample obtained from the individual is increased relative to a reference level; (b) the expression and / or activity of Traf2 in a biological sample obtained from the individual is increased relative to a reference level; and / or (c) the expression and / or activity of Dido1 in a biological sample obtained from the individual is decreased relative to a reference level, and the method further includes administering one or more additional doses of an agent to the individual, wherein the agent decreases the expression and / or activity of Cebpb; decreases the expression and / or activity of Traf2; and / or increases the expression and / or activity of Dido1.

[0529] In some aspects, (a) the expression and / or activity of Cebpb in a biological sample obtained from the individual is reduced relative to a reference level; (b) the expression and / or activity of Traf2 in a biological sample obtained from the individual is reduced relative to a reference level; and / or (c) the expression and / or activity of Dido1 in a biological sample obtained from the individual is increased relative to a reference level, and the method further includes administering one or more additional doses of an agent to the individual, wherein the agent increases the expression and / or activity of Cebpb; increases the expression and / or activity of Traf2; and / or decreases the expression and / or activity of Dido1.

[0530] VII. Methods for adjusting the processing of NFKB1 and / or NFKB2

[0531] A. Methods for treating cancer, inflammatory diseases, or autoimmune diseases

[0532] In some aspects, this disclosure is characterized by a method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering to the individual an effective amount of a modulator of the interaction between (a) an F-box and WD repeat domain 11 (Fbxw11) and (b) nuclear factor κB subunit 1 (Nfkb1) or nuclear factor κB subunit 2 (Nfkb2).

[0533] In some respects, the modulator is a modulator as described in Part II of this document, for example, a proteolytic targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment (e.g., bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, bispecific antibody, linear antibody, scFv, scFab, VH domain or VHH domain) (e.g., an antibody or its antigen-binding fragment that binds to one, two or all three of Fbxw11, Nfkb1 and Nfkb2), a peptide, a mimic or a repressive nucleic acid (e.g., ASO or siRNA).

[0534] In some respects, the individual has cancer, and the modulator is a drug that increases the expression and / or activity of Fbxw11.

[0535] In some respects, the individual suffers from an inflammatory disease or an autoimmune disease, and the modulator is an agent that reduces the expression and / or activity of Fbxw11.

[0536] In some respects, inflammatory or autoimmune diseases are neurodegenerative diseases (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD)), arthritis, allergies, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some respects, inflammatory or autoimmune diseases are Crohn's disease. In some respects, inflammatory or autoimmune diseases are encephalitis, myelitis, meningitis, arachnoiditis, neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillary inflammation, sinusitis, rhinitis. Pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleurisy, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, salivary gland inflammation / mumps, cheilitis, pulpitis, jaw inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, appendicitis, proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis.

[0537] Folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, origin-entry point inflammation, fasciitis, bursitis, epicondylitis, tendinitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis.

[0538] Balanitis, posthitis, balanoposthitis, chorioamnionitis, omphalitis, pancreatitis, pituitary inflammation, thyroiditis, parathyroiditis, adrenalitis, lymphangitis or lymphadenitis.

[0539] B. Methods for adding Nfkb1 and / or Nfkb2 processing

[0540] In some aspects, this disclosure is characterized by a method for increasing the processing of Nfkb1 and / or Nfkb2 into an active form, the method comprising contacting cells capable of expressing Fbxw11 with an agent that increases the expression and / or activity of Fbxw11.

[0541] Agents that increase the expression and / or activity of Fbxw11 may be, for example, PROTACs; small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bimeric antibodies, linear antibodies, scFv, scFab, VH domain or VHH domain) (e.g., antibodies or antigen-binding fragments thereof that bind to Fbxw11); peptides; mimics; or repressive nucleic acids (e.g., ASO or siRNA).

[0542] In some individuals, cells capable of expressing Fbxw11 exist. In other individuals, the individual may have cancer.

[0543] In some aspects, the processing of Nfkb1 into its active form increases by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more than 100% relative to the processing of Nfkb1 into its active form in the absence of the drug (e.g., an increase of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100% relative to the processing of Nfkb1 into its active form in the absence of the drug). In some aspects, the processing of Nfkb1 into its active form in an individual increases by at least 10% relative to the processing of Nfkb1 into its active form in the absence of the drug.

[0544] In some aspects, the processing of Nfkb2 into its active form increases by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more than 100% relative to the processing of Nfkb2 into its active form in the absence of the drug (e.g., an increase of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, 95%-100%, or more than 100% relative to the processing of Nfkb2 into its active form in the absence of the drug). In some aspects, the processing of Nfkb2 into its active form in an individual increases by at least 10% relative to the processing of Nfkb2 into its active form in the absence of the drug.

[0545] C. Processing methods to reduce Nfkb1 and / or Nfkb2

[0546] In some aspects, this disclosure is characterized by a method for reducing the processing of Nfkb1 and / or Nfkb2 into an active form, the method comprising contacting cells capable of expressing Fbxw11 with an agent that reduces the expression and / or activity of Fbxw11.

[0547] Agents that reduce the expression and / or activity of Fbxw11 can be, for example, PROTACs; small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bisomatic antibodies, linear antibodies, scFv, scFab, VH domain or VHH domain) (e.g., antibodies or antigen-binding fragments thereof that bind to Fbxw11); peptides; mimics; or inhibitory nucleic acids (e.g., ASO or siRNA).

[0548] In some individuals, cells capable of expressing Fbxw11 exist. In some individuals, the individual suffers from an inflammatory disease or an autoimmune disease. In some cases, the inflammatory disease or autoimmune disease is a neurodegenerative disease (e.g., MS, AD, ALS, or PD), arthritis, allergic reactions, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some cases, the inflammatory disease or autoimmune disease is Crohn's disease. In some respects, inflammatory or autoimmune diseases include encephalitis, myelitis, meningitis, arachnoiditis, neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillary inflammation, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleurisy, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, salivary gland inflammation / parotitis, cheilitis, pulpitis, jaw inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, cecal inflammation, and appendicitis. Proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, origin-endocrine inflammation, fasciitis, bursitis, epicondylitis, tendinitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, posthitis, balanoposthitis, chorioamnionitis, omphalitis, pancreatitis, pituitary inflammation, thyroiditis, parathyroiditis, adrenalitis, lymphangitis or lymphadenitis.

[0549] In some aspects, Nfkb1 is processed into its active form at a reduction of at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% relative to the amount of Nfkb1 processed into its active form in the absence of the drug (e.g., a reduction of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100% relative to the amount of Nfkb1 processed into its active form in the absence of the drug). In some aspects, Nfkb1 is processed into its active form in an individual at a reduction of at least 10% relative to the amount of Nfkb1 processed into its active form in the absence of the drug.

[0550] In some aspects, Nfkb2 is processed into its active form at a reduction of at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% relative to the active form in the absence of the drug (e.g., a reduction of 5%-15%, 15%-25%, 25%-35%, 35%-45%, 45%-55%, 55%-65%, 65%-75%, 75%-85%, 85%-95%, or 95%-100% relative to the active form in the absence of the drug). In some aspects, Nfkb2 is processed into its active form in an individual at a reduction of at least 10% relative to the active form in the absence of the drug.

[0551] D. Methods to enhance immune responses guided by NfKb1 and / or NfKb2

[0552] In another aspect, this disclosure is characterized by a method for increasing an immune response directed by Nfkb1 and / or Nfkb2 in an individual (e.g., an individual with cancer), the method comprising administering to the individual an effective amount of an agent that increases the expression and / or activity of Fbxw11.

[0553] Agents that increase the expression and / or activity of Fbxw11 may be, for example, PROTACs; small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bimeric antibodies, linear antibodies, scFv, scFab, VH domain or VHH domain) (e.g., antibodies or antigen-binding fragments thereof that bind to Fbxw11); peptides; mimics; or repressive nucleic acids (e.g., ASO or siRNA).

[0554] E. Methods to reduce immune responses directed by Nfkb1 and / or Nfkb2

[0555] In another aspect, this disclosure is characterized by a method for reducing an immune response directed by Nfkb1 and / or Nfkb2 in an individual (e.g., an individual suffering from an inflammatory disease or an autoimmune disease), the method comprising administering to the individual an effective amount of an agent that reduces the expression and / or activity of Fbxw11.

[0556] Agents that reduce the expression and / or activity of Fbxw11 can be, for example, PROTACs; small molecules; antibodies or antigen-binding fragments thereof (e.g., bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, bisomatic antibodies, linear antibodies, scFv, scFab, VH domain or VHH domain) (e.g., antibodies or antigen-binding fragments thereof that bind to Fbxw11); peptides; mimics; or inhibitory nucleic acids (e.g., ASO or siRNA).

[0557] In some respects, inflammatory or autoimmune diseases are neurodegenerative diseases (e.g., MS, AD, ALS, or PD), arthritis, allergies, eczema, fibrosis, asthma, lupus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some respects, inflammatory or autoimmune diseases are Crohn's disease. In some respects, inflammatory or autoimmune diseases include encephalitis, myelitis, meningitis, arachnoiditis, neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillary inflammation, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleurisy, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, salivary gland inflammation / parotitis, cheilitis, pulpitis, jaw inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, cecal inflammation, and appendicitis. Proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, origin-endocrine inflammation, fasciitis, bursitis, epicondylitis, tendinitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, posthitis, balanoposthitis, chorioamnionitis, omphalitis, pancreatitis, pituitary inflammation, thyroiditis, parathyroiditis, adrenalitis, lymphangitis or lymphadenitis.

[0558] F. Combination therapy

[0559] Any method in Parts VII(A) through VII(E) may further include administering one or more additional agents to an individual or cell capable of expressing Fbxw11 (e.g., administering one or more additional agents before, during, or after treatment with a modulator of the interaction between (a) Fbxw11 and (b) Nfkb1 or Nfkb2, an agent that increases the expression and / or activity of Fbxw11, or an agent that decreases the expression and / or activity of Fbxw11).

[0560] In some respects, additional agents are agents that regulate the expression of one or more members of module M5 as presented in Example 3, such as those regulating Acaca, Ambra1, Amfr, Arih1, Cbll1, Cfap57, Cnot4, Cyld, Dcaf7, Det1, Dpf2, Eed, Efcab8, Egr2, Fasn, Fbxw7, Foxo3, Gsk3b, Hectd3, Hira, Icos, Ifnar1, Ikbke, Ints12, Junb, Kat6a, Kctd10, Kctd13, Kct One or more of the following expressions: d21, Kctd5, Klhl30, Klhl6, Lztr1, March6, Msl2, Nf1, Nsd1, Patz1, Pias1, Prdm1, Pten, Rfwd2, Rnf139, Socs3, Spag16, Strap, Stub1, Syk, Tab1, Tank, Tbk1, Tnf, Trim45, Trip12, Ube2j2, Wdfy2, Wdr61, Wdr81, Wdr91, Zbtb25, Zfp106, Zfp91, and Zmiz2.

[0561] In some respects, additional agents are agents that regulate the expression of one or more members of module M6 as presented in Example 3, such as those regulating Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fus, Gm9840, Hif1a, Huwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, R Expressions of one or more of the following: anbp2, Rbbp6, Rbck1, Rbx1, Rc3h1, Rela, Rlim, Rnf144a, Rnf31, Rnf7, Seh1l, Skp1a, Spop, Ssr3, Tbl1xr1, Tceb1, Tceb2, Tceb3, Tdpoz5, Thoc3, Tlr4, Traf6, Trim28, Trim33, Ube2d3, Ube2f, Ube2h, Ube2i, Ubr4, Ubr5, Vhl, Wdr20, Wdr26, Wdr33, Zbtb17, and Zbtb7b.

[0562] G. Methods for monitoring response to treatment

[0563] In another aspect, this disclosure is characterized by a method for monitoring the response of an individual suffering from cancer, an inflammatory disease, or an autoimmune disease to treatment with a modulator of the interaction between (a) Fbxw11 and (b) Nfkb1 or Nfkb2, the method comprising: (i) determining the expression level of an active form of one or both of Nfkb1 and Nfkb2 in a biological sample obtained from the individual at a time point following administration of the modulator; and (ii) comparing the expression level of an active form of one or both of Nfkb1 and Nfkb2 in the biological sample with a reference level, thereby monitoring the individual's response to treatment with the modulator.

[0564] In some respects, the reference level is selected from the group consisting of: (i) the expression levels of one or two genes in a biological sample obtained from an individual prior to the administration of the regulator; (ii) the expression levels of one or two genes in a reference population; (iii) a pre-specified expression level for one or two genes; or (iv) the expression levels of one or two genes in a biological sample obtained from an individual at a previous time point, wherein the previous time point is after the administration of the regulator.

[0565] In some respects, the individual has cancer, the expression level of one or both of the active forms of Nfkb1 and Nfkb2 in a biological sample obtained from the individual is reduced relative to a reference level, and the method further includes administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that increases the expression and / or activity of Fbxw11.

[0566] In some respects, the individual suffers from an inflammatory disease or an autoimmune disease, the expression level of one or both of the active forms of Nfkb1 and Nfkb2 in a biological sample obtained from the individual is increased relative to a reference level, and the method further includes administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that reduces the expression and / or activity of Fbxw11.

[0567] VIII. Cell Therapy

[0568] A. Methods of treating cancer, inflammatory diseases, or autoimmune diseases using cell therapy.

[0569] In some aspects, this disclosure is characterized by a method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering to the individual an effective amount of a cell therapy comprising cells containing alterations to at least two genes from one or more of the following cofunctional gene modules:

[0570] (a) Module M1, which includes Aamp, Bop1, Cirh1a, Dcaf13, Grb2, Myc, Nle1, Nol10, Pak1ip1, Ptpn11,

[0571] Rack1, Raf1, Rrp9, Taf5, Tbl3, Uhrf1, Utp15, Utp18, Vprbp, Wdr3, Wdr36, Wdr43, Wdr5, Wdr74 and Wdr75;

[0572] (b) Module M2, which includes Ago2, Ahr, Anapc13, Bach1, Baz1a, Bid, Bptf, Brca1, Brwd3, Btbd1, Cblc, Ccnf, Cdc27, Cntn4, Copa, Copb2, Coro1a, Cpne9, Cul4b, Ddb1, Dido1, E4f1, Ecel1, Fbxl14, Fbxl5, Fbxo11, Fbxo42, Fzr1, Gemin5, Gm10697, Gm9117, Gtf2h2, Gtf3c1, Hdac4, Hectd1, Ift122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23, Klhl3, Kmt2b, LOC100861784, Lrr1, Lrrc41, Map3k7, Mdm4, Mib1, Mkrn1, Mnat1, Naca, Nsmaf, Ogt, Pa2g4, Pcif1, Ppp1r11, Prc1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah2, Taf3, Tdpoz2, Tmem183a, Tnfsf11, Tradd, Traf3ip2, Trim35, Trim7, Tssc1, Ttc3, Ube2n, Ufl1, Unkl, Upf1, Vdr, Wdhd1, Wdr48, Wdr95, Wwp1, Ybx1, Zbtb14, Zbtb49, Zbtb7a and Zmiz1;

[0573] (c) Module M3, which includes Akt1, Ankfy1, Apc, Arcc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbxl13, Fbxo28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, Mlst8, Mtor, Nosip, Paf1, Pik3r4, Pparg, Ppp2r2a, Ppp2r2d, Preb, Rbbp4, Rbbp5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13, S ec31a, Smad2, Syvn1, Taf5l, Traf2, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1 and Zbtb11;

[0574] (d) Module M4, which includes Cdc40, Ddx41, Plrg1, Ppil2, Ppwd1, Prpf19, Prpf4, Sart1, Smu1, Snrnp40 and Wdr70;

[0575] (e) Module M5, which includes Acaca, Ambra1, Amfr, Arih1, Cbll1, Cfap57, Cnot4, Cyld, Dcaf7, Det1, Dpf2, Eed, Efcab8, Egr2, Fasn, Fb xw7, Foxo3, Gsk3b, Hectd3, Hira, Icos, Ifnar1, Ikbke, Ints12, Junb, Kat6a, Kctd10, Kctd13, Kctd21, Kctd5, Klhl30, Klhl6, Lztr1, March6, Msl2, Nf1, Nfkb1, Nsd1, Patz1, Pias1, Prdm1, Pten, Rfwd2, Rnf139, Socs3, Spag16, Strap, Stub1, Syk, Tab1, Tank, Tbk1, Tnf, Trim45, Trip12, Ube2j2, Wdfy2, Wdr61, Wdr81, Wdr91, Zbtb25, Zfp106, Zfp91 and Zmiz2; and

[0576] (f) Module M6, which includes Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fbxw11, Fus, Gm9840, Hif1a, Huwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, Ranbp2, Rbb p6, Rbck1, Rbx1, Rc3h1, Rela, Rlim, Rnf144a, Rnf31, Rnf7, Seh1l, Skp1a, Spop, Ssr3, Tbl1xr1, Tceb1, Tceb2, Tceb3, Tdpoz5 , Thoc3, Tlr4, Traf6, Trim28, Trim33, Ube2d3, Ube2f, Ube2h, Ube2i, Ubr4, Ubr5, Vhl, Wdr20, Wdr26, Wdr33, Zbtb17 and Zbtb7b.

[0577] For example, the cell may contain (1) changes in at least two genes in the genes of module M1 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in the genes of module M1); (2) changes in at least two genes in the genes of module M2 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in the genes of module M2); and (3) changes in at least two genes in the genes of module M3 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in the genes of module M3). (4) Changes in at least two genes in the genes of module M4 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten or more genes in the genes of module M4); (5) Changes in at least two genes in the genes of module M5 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten or more genes in the genes of module M5); or (6) Changes in at least two genes in the genes of module M6 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten or more genes in the genes of module M6).

[0578] In some respects, the cell contains alterations to at least two genes in the first module and one or more genes in the second module, for example, alterations to at least two genes in the genes of module M1 and at least one gene in the genes of any of modules M2 to M6.

[0579] In some respects, the cell contains alterations to at least two genes in the first module and at least two genes in the second module, for example, alterations to at least two genes in the genes of module M1 and at least two genes in the genes of any of modules M2 to M6.

[0580] In some aspects, this disclosure is characterized by a method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering to the individual an effective amount of a cell therapy comprising cells containing alterations to at least two genes from one or more of the following gene sets:

[0581] (a) Gene set 1, which includes Aamp, Actb, Alcam, Ambra1, Anxa2, Aprt, Atp5e, B2m, Btf3, Ccdc88a, Cdh1, Chd4, Cirh1a, Cox4i1, Cox7a2l, Crebbp, Ctsb, Dcaf13, Ddx41, Eef1a1, Eef1b2, Eef1g, Eef2, Eif1, Eif3e, Eif3f, Eif3i, Eif3k, Fau, Gapdh, H2-D1, H2-K1, H2-M2, Hsp90ab1, Hspa 5. Hspa8, Il1rn, Laptm5, Lhfpl2, March6, Ms4a7, Mtor, Myc, Naca, Ncl, Nf1, Nol10, Npm1, Ogt, Pabpc1, Paf1, Plrg1, Pparg, Psap, Rac k1, Raf1, Rheb, Rpl10, Rpl10a, Rpl11, Rpl12, Rpl13, Rpl13a, Rpl14, Rpl15, Rpl17, Rpl18, Rpl18a, Rpl19, Rpl21, Rpl22, Rpl22l1, Rp l23, Rpl23a, Rpl24, Rpl26, Rpl27a, Rpl28, Rpl29, Rpl3, Rpl30, Rpl31, Rpl32, Rpl34, Rpl35, Rpl35a, Rpl36, Rpl36a, Rpl37, Rpl37a, Rpl38, Rpl39, Rpl4, Rpl41, Rpl5, Rpl6, Rpl7, Rpl7a, Rpl8, Rpl9, Rplp0, Rplp1, Rplp2, Rps10, Rps11, Rps12, Rps13, Rps14, Rps15, Rp s15a, Rps16, Rps17, Rps18, Rps19, Rps2, Rps20, Rps21, Rps23, Rps24, Rps25, Rps26, Rps27, Rps27a, Rps28, Rps29, Rps3, Rps3a1, Rps 4x, Rps5, Rps6, Rps7, Rps8, Rps9, Rpsa, Rptor, Sgk1, Ssr4, Tab1, Taf5, Tpt1, Uhrf1, Uqcrh, Utp15, Wdr3, Wdr36, Wdr43, Wdr5 and Zbtb25;

[0582] (b) Gene set 2, which includes AI314180, Abcc1, Acod1, Akr1a1, Alas1, Alox5ap, Ampd3, Arih1, Ass1, B430306N03Rik, Bach1, Blvrb, Bmi1, Brca1, Btbd1, Btg1, Cat, Ccr5, Cd36, Cd52, Cd53, Cd81, Chd4, Chpf2, Clec4n, Crebbp, Creg1, Cul3, Cx cl3, Cyb5a, Dap, Dars, Dck, Ddb1, Ddit3, Egr2, Eif3f, Eif3i, Ep300, Esd, Fbxl5, Fbxw11, Gbe1, Gclm, Gdap10, G m9840, Gss, Gstm1, H3f3b, Hmox1, Hvcn1, Il1f9, Inhba, Keap1, Lipa, Lmo4, Map3k7, Mcl1, Mcoln2, Met, Mgst2, Mm p12, Mmp19, Mmp8, Mylip, Nampt, Nedd8, Nf1, Npy, Nrp1, Nup43, Nupr1, Paf1, Pf4, Pgd, Phlda1, Pla2g7, Plet1, P pfibp2, Prdx1, Prdx6, Preb, Prkcb, Procr, Ptgr1, Ptpn1, Raf1, Rbx1, Rhob, Rnasel, Rnf128, Runx2, Sdc4, Sec13 , Seh1l, Skp1a, Slc43a2, Slc48a1, Slc7a11, Slpi, Smad2, Srxn1, Taldo1, Tarm1, Thbs1, Tlr2, Tlr4, Tma16, Tpm 4. Traf2, Traf5, Traf6, Trip12, Tubb2a, Txnrd1, Ube2d3, Ube2n, Ubr5, Uchl1, Upf1, Wdr43, Wdr61, Zbtb17 and Zyx;

[0583] (c) Gene set 3, which includes Acp5, Ankfy1, Arpc1b, Atp6v0d2, Bptf, Brap, C5ar1, Ccdc88a, Cd14, Cd36, Cd63, Cebpb, Chd4, Clec4d, Clec5a, Cpd, Creg1, Ctsb, Ctsz, Cul3, Ddhd1, Dnmt3a, Egr2, Emb, and F6300. 28O10Rik, Fabp5, Fam46c, Fbxo42, Fcgr2b, Fn1, Foxo3, Fpr1, Ftl1, Gadd45a, Glrx, Gpnmb, Gp r84, Huwe1, Icam1, Id1, Il1f9, Kctd10, Keap1, Klhl6, Lcn2, Lgals1, Lgals3, Lgmn, Lipa, Lpca t2, Ly6c2, March6, Metrnl, Mgll, Mt1, Mtor, Myof, Naaa, Naca, Nf1, Paf1, Phlda1, Pid1, Pik3 r4, Pld3, Plet1, Plk2, Pou2f2, Pparg, Prdx5, Psap, Ptpn11, Rab3il1, Rela, Rfwd2, Rnase2a, S 100a1, S100a11, S100a8, Saa3, Sdc3, Serpinb2, Slamf7, Snx18, Sod2, Spata13, Stap1, Strap, Tab1, Tceb2, Tgfbi, Thbs1, Trem1, Upf1, Upp1, Vat1, Wdfy3, Wfdc21, 2010005H15Rik and Zbtb25;

[0584] (d) Gene set 4, which includes AC160336.1, Actb, Actg1, Ankfy1, Arhgdib, Bptf, Brap, Bri3, Ccr2, Ccr5, Cd274, Cdkn1a, Cfl1, Chd4, Clec4a2, Copa, Coro1a, Cotl1, Crip1, Cul1, Cul3, Dars, Ddhd1, Ddit3, Ear2, Eif3f, Eif3i, Ep300, Fbxw11, Flna, Gbp2, Gbp5, Grb2, Gtf3c1, H2-D1, H2-K1, Huwe1, If i27l2a, Il1rn, Keap1, Klk1b1, Lcp1, Lgals1, Lpl, Lrr1, Lsp1, Malat1, Marcksl1, Med8, Mgll, Mndal, Mtor, Naca, Nedd8, Nf1, Paf1, Pfn1, Pi k3r4, Pten, Ptma, Ptpn11, Rack1, Rela, Rnf20, Sdc4, Skp1a, Taf3, Taf5, Tlr4, Tmsb4x, Ubb, Ube2i, Upf1, Vhl, Wdfy3, Wdr43, Wdr82 and Wfdc17;

[0585] (e) Gene set 5, which includes AA467197, AW112010, Abcg1, Acod1, Bcl2a1b, Bcl2a1d, Cav1, Ccl17, Ccl3, Ccl4, Cd14, Cd200r1, Cd300lf, Cdkn1a, Cebpb, Cflar, Chd4, Clec4e, Clic4, Copa, Cpd, Cpeb4, Cul1, Cul3, Cx cl1, Cxcl2, Cxcl3, Ehd1, Ep300, Fam102b, Fam20c, Fbxw11, Gda, Gpr84, Hist1h1c, Hivep3, Ikbke, I kbkg, Il12b, Il1a, Il1b, Il6, Ing3, Inhba, Kctd21, Klf4, Laptm5, Mafb, Malat1, Malt1, Marcks, Ma rcksl1, Marco, Met, Mtpn, Nabp1, Nedd8, Nfkb1, Nfkbiz, Nlrp3, Nrp2, Nup62, Ogt, Paf1, Plek, Plrg 1. Ppfia3, Prpf19, Ptgs2, Ptx3, Rassf4, Rbx1, Rela, Rfwd2, Rnf31, Serpinb2, Sh3bp5, Skp1a, Slc7 a11, Slc7a2, Slco3a1, Slfn2, Smad2, Smu1, Socs6, Sod2, Spop, Stub1, Tank, Tbk1, Tceb3, Tlr4, Tnf , Tnfaip3, Tnfsf15, Tradd, Traf6, Trip12, Txnip, Ube2d3, Ube2i, Ube2n, Wdr82, Zbtb17 and Zc3h12c;

[0586] (f) Gene set 6, which includes AA467197, Ahr, Akt1, Ankfy1, Axl, Bhlhe40, Bhlhe41, Btg1, Ccl17, Ccl22, Ccr2, Cd40, Cd52, Cd74, Cebpb, Chd4, Clec4e, Clec4n, Clic4, Cst3, Cstf1, Ctsb, Ctsd, Cxcl16. Dcstamp, Egr2, Etv3, Fabp4, Fabp5, Fam20c, Fbxw7, Fbxw9, Foxo3, Fpr1, Fth1, Ftl1, Gbp2, G bp5, Gm2a, Gnb1, Gnb2, Grb2, Grk3, Gsk3b, H2-Aa, H2-Ab1, Hmox1, Igf1, Il4i1, Irf4, Itgax, J ak2, Jund, Kcmf1, Klhl6, Kmt2d, Lgals1, Lyz2, March6, Mgl2, Mmp12, Mtor, Myc, Ndufa4, Nec tin2, Nf1, Nfkb1, Pfkp, Pid1, Pik3r4, Plet1, Pmp22, Pten, Ptpn1, Ptpn11, Rheb, Rilpl2, Rp tor, S100a8, Sart1, Scimp, Sdcbp, Sema4a, Sgk1, Slamf9, Smad2, Srgn, Stat5a, Tab1, Taf5l , Tank, Tceb1, Tceb2, Tlr2, Tlr4, Traf2, Traf3, Ube2n, Vcan, Wdfy3, Wdr26, Wdr61 and Zfp36l1;

[0587] (g) Gene set 7, which includes Abca1, Actb, Ambra1, Atf4, Atp5g1, Atp5j, Atp5j2, Bcl2a1b, Calm1, Cfl1, Chd4, Copa, Copb2, Cotl1, Cox8a, Cul3, Cybb, Dbi, Ddit3, Eef1a1, Eif3f, Eif3i, Fbxo28, Fcer1g, Gpx1, Grb2, H2-M2, H2afz, H3f3a, Il1rn, Inhb a, Keap1, Kmt2d, Lhfpl2, Ly6e, March6, Med8, Mtor, Nedd8, Nf1, Nme1, Ogt, Paf1, Plrg1, Pnp, Pparg, Rack1, S100a10 , S100a4, S100a6, Sdc4, Sec13, Serf2, Sgk1, Smad2, Smu1, Sqstm1, Tab1, Taf3, Trp53, Uhrf1, Wdr43, Wdr61 and Zbtb25;

[0588] (h) Gene set 8, which includes Aamp, Acsl1, Ambra1, Arf4, Arih2, Atf4, Bop1, C1qb, Calr, Canx, Ccng1, Cdkn1a, Chd4, Cirh1a, Clec2d, Copa, Copb2, Cope, Cpd, Ctss, Cul3, Dad1, Dap, Dcaf13, Ddit3, Ddx41, Dstn, Eif 3f, Eif3i, Erp29, Fbxw7, Fth1, Ftl1, Gm9840, Grb2, Gtf3c1, Herpud1, Hif1a, Hnrnpa3, Hsp90b1, Hs pa5, Ift20, Keap1, Kmt2d, Krtcap2, Lgals3, Lrr1, Lyz2, Manf, Map3k7, Mthfd2, Mtor, Myc, Naca, Ne dd8, Nf1, Nol10, Ostc, P4hb, Pdia3, Pdia4, Pdia6, Phgdh, Plrg1, Preb, Prpf19, Pten, Ptpn1, Rack1 , Rbx1, Rela, Rpl22l1, Rpn1, Rps19, Rrp9, Sdf2l1, Sec11c, Sec13, Sec22b, Sec31a, Sec61b, Sec61g , Selenos, Serf2, Serp1, Sf3b5, Spcs2, Ssr3, Surf4, Syvn1, Tceal9, Tceb1, Tceb2, Timm13, Tpt1, T ram1, Trp53, Ube2f, Ufm1, Uqcrq, Utp15, Vcp, Vhl, Vprbp, Wdr36, Wdr43, Wdr5, Wdr74, Wdr75 and Xbp1;

[0589] (i) Gene set 9, which includes Acod1, Adam8, Atp5g3, Brap, C3ar1, Ccl2, Ccl3, Ccl4, Ccl7, Ccnd1, Cd300ld, Cd63, Ch25h, Chd4, Chil3, Crip1, Ctsb, Ctsl, Cul1, Cul3, Cxcl1, Cyp51, Det1, Ear2, Egr2, F10, Fbxo42, F bxw11, Ffar2, Fpr2, Fyb, Gas7, Gm9840, Gnb2, Gpnmb, Grb2, Gsk3b, Hmgcs1, Huwe1, Ifitm3, Il1f9, Itgam, Jun, Kctd12, Kctd5, Keap1, Klhdc4, Kmt2c, Kmt2d, Lgals1, Lgals3, Lmna, Lmo4, Lrpap1, Ly6 c2, Lztr1, Maf, March6, Mcemp1, Mmp12, Mmp13, Mmp8, Msr1, Mtor, Naaa, Naca, Nf1, Nfkbiz, Npc2, N py, Paf1, Pdpn, Pf4, Plet1, Pparg, Prkcd, Pten, Ptgs2, Ptpn1, Ptpn11, Ptprc, Ptx3, Rbbp5, Rela, R fwd2, Rheb, Rptor, S100a6, Saa3, Scap, Scd2, Serpinb2, Serpinb6a, Sgk1, Slc7a11, Smad2, Srgn, Syk, Syngr1, Timp2, Trem2, Ube2h, Ube2i, Ucp2, Vasp, Vhl, Wdr26, Wfdc21, Ybx1, Zbtb7a and Zfp36l2;

[0590] (j) Gene set 10, which includes Acaca, Ak4, Aldoa, Aldoc, Anapc13, Anxa2, Arih2, Arnt, Basp1, Bnip3l, Bsg, C3ar1, Ccl9, Cd52, Chil3, Copa, Cul2, Cul3, Cul5, Egr2, Eif3i, Eif4ebp1, Emilin2, Eno1, Ep300, Fam162a, Gapdh, Gbe1, Gpi1, Gsn, Herpud1, Hif1a, Higd1a, Hilpda, Hk1, Hk2, Hmox1, Huwe1, Ier3, Kctd10, Klk1b1, Ldha, Lgals3, Lipa, Lmo4, Lpcat2, L yz2, March6, Mif, Mt1, Mt2, Mtor, Myc, Ndufv3, Nf1, Pdk1, Pfkl, Pgam1, Pgk1, Pgm2, P km, Prdx1, Prelid1, Ptpn1, Ptpn11, Rbpj, Rfwd2, Rilpl2, Rnase2a, Sacs, Scd2, Sdc3, Sdc4, Sec13, Slamf9, Slc16a3, Slc2a1, Slc7a2, Smu1, Socs3, Strap, Tarm1, Tceb1, T ceb2, Tgm2, Tlr4, Tpi1, Trf, Ube2f, Vhl, Vim, Wdr43, Wdr82, Wfdc17 and 2010005H15Rik;

[0591] (k) Gene set 11, which includes AA467197, Apobec1, Apoe, C1qa, C1qb, C1qc, C3, Car4, Ccl22, Ccl3, Ccl4, Ccl6, Ccl9, Cd83, Cdc40, Cebpb, Ch25h, Chd4, Copa, Crebbp, Cul1, Ddhd1, Ddx41, Egr2, Eif3f, Eif3i, Ep300, Fam49a, Fbxw11, Fn1, Fnbp1l, Gadd45b, Hdac4, Icam1, Icosl, Id2, Ikbkg, Il1a, Il4i1, Inhba, Itgax, Itgb2, Kctd10, Klk1b11, Lpl, Maf, Marks, Marksl1, M ed8, Met, Mmp12, Ms4a6c, Ms4a7, Mt2, Mycbp2, Naca, Nedd8, Nfkbia, Phlda1, Plaur, Plrg1, Pparg, Ppfibp2, Prpf19, Ptpn1, Rassf4, Rfwd2, Ring1, Rnase2a, Rpl12, Scimp, Sec13 ,Skp1a,Slc43a2,Smu1,Sqstm1,Syk,Syvn1,Taf5l,Tceb2,Tmem176a,Tmem176b,Tnfaip 2. Traf3, Ufm1, Upp1, Wdr5, Wdr70, Wdr82, Wfdc17, Wfdc21, 0610012G03Rik, Zbtb7a and Zyx;

[0592] (l) Gene set 12, which includes Ambra1, Aplop2, Atp5g1, Atpif1, B2m, Ccdc88a, Chd4, Copa, Cyba, Ddit3, Ear2, Egr2, Eif3f, Eif3i, Eif5, Fcgrt, Grn, H2-M2, H2-Q6, Hint1, Id1, Ifi204, Itgal, Kctd12, Laptm5, Lgals3, Ly6e, Mgst1, Mpeg1, Mtdh, Nf1 Nfe2l2, Nupr1, Paf1, Pparg, Prpf19, Psmb5, Psmb6, Pycard, Rack1, Rnase4, Rpl22l1, Rpl37a, Rplp0, Sart1, Sdc3, S ec61b, Smad2, Smdt1, Smu1, Spp1, Syvn1, Tab1, Taf5, Taf5l, Tagln2, Tmsb10, Traf2, Traf3, Trf, Trp53, Upf1 and Wdr5;

[0593] (m) Gene set 13, which includes Ankfy1, Anxa1, Anxa5, Aph1c, Brap, C3ar1, Ccnd2, Ccr1, Cd300lf, Cd38, Cd68, Cd9, Cdc27, Cdc40, Cebpb, Chd4, Chst11, Clec4e, Creb5, Cul1, Cul3, Cxcl3, Cyba, Dstn, Eif3f, Eif3i, Emp1, Epha4, Fam102b, Fam46a, Fbxw11, Fn1, Foxo3, Ftl1, Furin, Gas7, Gdf15, Grb2, H2-K1, Huwe1, Icam1, Il7r, Inhba, Keap1, Klhdc4, Klk1b11, Lgal s3, Lpl, Ly6c2, Lyz2, March6, Mbnl1, Mmp14, Mmp8, Ms4a7, Naca, Neat1, Nf1, Nrp2, Pli n2, Plk2, Plrg1, Polr2l, Prdx1, Pten, Ptpn1, Rack1, Rasgef1b, Rasgrp1, Rela, Rnf20, Rnh1, Rpl22l1, Rrp9, Saa3, Scd2, Sdc4, Sec13, Selenoh, Serp1, Skp1a, Slamf7, Slc7a2 , Smu1, Spp1, Tab1, Taf5, Ube2d3, Ubr4, Upf1, Vim, Wdr43, Wdr5, Wdr70, Wdr82 and Zbtb25;

[0594] (n) Gene set 14, which includes AC160336.1, Adgre1, Adgre4, Adgrl2, Anxa1, B2m, C1qb, C3, Car4, Ccdc88a, Ccl6, Cd52, Cdc40, Chd4, Chil3, Crip1, Ctsk, Ddx41, Dpf2, Egr2, Eif3i, Ep300, F7, Fcer1g, Fn1, Foxo3, Gpx3, H2-D1, H2-K1, H2-Q6, H2-Q7, H3f3b, Hira, Hsp90aa1, Hvcn1, Id2, Ifi203, Il18, Il1f9, Kdm5c, Klhl6, Lgals1, Lgals3, Ly6e, Malt1, March6, Marks. Mcub, Med8, Mpc1, Ms4a6d, Msrb1, Mt1, Mt2, Nedd8, Nfe2l2, Nov, Npc2, Paf1, Pdzk1ip1, Phgdh, Pias1, Pla2g7, Plrg1, Ppic, Ppil2, Ppwd1, Prkcd, Prpf19, Ptges, Rab32, Rbx1, and

[0595] (o) Gene set 15, which includes AC160336.1, Adgre1, Ahnak, Alcam, Aprt, Bcl2l11, Blvrb, Brap, Bub3, C1qb, C1qc, C3ar1, Cd300c2, Cd33, Cd68, Cdc40, Cebpb, Chchd2, Clec12a, Clec4n, Copa, Csf1r, Ctsz, Cul3, Cul5, Cyba, Ddx41, Dstn, Egr2, Ep300, F7, Fbxw7, Fcer1g, Fcgr2b, Gmfg, Gngt2, Gpr84, Hsp90aa1, Huwe1, Igf1, Kat6a, Kctd12b, Kdm5c, Keap1, Kmt2d, Ls t1, Mmp14, Mpeg1, Myc, Naca, P2ry14, Paf1, Pirb, Plrg1, Pou2f2, Pparg, Ppil2, Ppwd1 , Prkcd, Prpf19, Prpf4, Ptpn1, Ptpn18, Rack1, Rbbp5, Rnf20, Rnf40, Rnf7, Rps27l, Sat 1. Serpinb2, Smu1, Socs3, Spp1, Taf5, Tank, Tceb1, Tceb2, Tgm2, Tnfsf15, Traf2, Tre m2, Tyrobp, Ufm1, Vcan, Wdr1, Wdr33, Wdr43, Wdr5, Wdr61, Wdr70, Wdr82, Wfdc21 and Ybx1.

[0596] For example, a cell may contain (1) changes in at least two genes in gene set 1 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 1); (2) changes in at least two genes in gene set 2 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 2); (3) changes in at least two genes in gene set 3 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 3); (4) changes in at least one gene in gene set 4. (5) Changes in at least two genes in gene set 4 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 5); (6) Changes in at least two genes in gene set 6 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 5); (7) Changes in at least two genes in gene set 7 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 7); (8) Changes in at least two genes in gene set 8 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 8); (9) Changes in at least two genes in gene set 9 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 9); (10) Changes in at least two genes in gene set 10 (e.g., changes in two, three, four, five, six, seven, eight, nine, or more genes in gene set 10). (11) Changes in at least two genes in gene set 11 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 11); (12) Changes in at least two genes in gene set 12 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 12); (13) Changes in at least two genes in gene set 13 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 13).(14) Changes in at least two genes in gene set 14 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 14); or (15) Changes in at least two genes in gene set 15 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 15).

[0597] In some respects, the cell contains alterations to at least two genes in a first gene set and one or more genes in a second gene set, for example, alterations to at least two genes in gene set 1 and at least one gene in any of gene sets 2 to 15.

[0598] In some respects, the cell contains alterations to at least two genes in the first module and at least two genes in the second module, for example, alterations to at least two genes in gene set 1 and at least two genes in any of gene sets 2 to 15.

[0599] The alteration can be a loss-of-function mutation (e.g., a mutation that results in a decrease or elimination of protein function, including deletion) or a gain-of-function mutation (e.g., a mutation that results in an increase in gene function, including gene duplication). For example, a cell containing alterations to two genes in module M1 may contain loss-of-function mutations in both genes; may contain gain-of-function mutations in both genes; or may contain a loss-of-function mutation in the first gene and a gain-of-function mutation in the second gene. In some aspects, at least one of the alterations is a loss-of-function alteration. In some aspects, at least one of the alterations is a gain-of-function alteration.

[0600] In some respects, this cell therapy is dendritic cell therapy, macrophage therapy, adoptive T-cell therapy (ACT), tumor-infiltrating lymphocyte (TIL) therapy, engineered T-cell receptor (TCR) therapy (TCR-T), chimeric antigen receptor T-cell (CAR-T) therapy, CAR-Treg therapy, or natural killer (NK) cell therapy.

[0601] B. Modified cells

[0602] On the other hand, this disclosure provides a genetically modified isolated cell comprising alterations to at least two genes in one or more of the following cofunctional gene modules:

[0603] (a) Module M1, which includes Aamp, Bop1, Cirh1a, Dcaf13, Grb2, Myc, Nle1, Nol10, Pak1ip1, Ptpn11,

[0604] Rack1, Raf1, Rrp9, Taf5, Tbl3, Uhrf1, Utp15, Utp18, Vprbp, Wdr3, Wdr36, Wdr43, Wdr5, Wdr74 and Wdr75;

[0605] (b) Module M2, which includes Ago2, Ahr, Anapc13, Bach1, Baz1a, Bid, Bptf, Brca1, Brwd3, Btbd1, Cblc, Ccnf, Cdc27, Cntn4, Copa, Copb2, Coro1a, Cpne9, Cul4b, Ddb1, Dido1, E4f1, Ecel1, Fbxl14, Fbxl5, Fbxo11, Fbxo42, Fzr1, Gemin5, Gm10697, Gm9117, Gtf2h2, Gtf3c1, Hdac4, Hectd1, Ift122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23, Klhl3, Kmt2b, L OC100861784, Lrr1, Lrrc41, Map3k7, Mdm4, Mib1, Mkrn1, Mnat1, Naca, Nsmaf, Ogt, Pa2 g4, Pcif1, Ppp1r11, Prc1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah2, Taf3, Tdpoz2, Tmem183a, Tnfsf11, Tradd, Traf3ip2, Trim35, Trim7, Tssc1, Ttc3, Ube2n, Uf l1, Unkl, Upf1, Vdr, Wdhd1, Wdr48, Wdr95, Wwp1, Ybx1, Zbtb14, Zbtb49, Zbtb7a and Zmiz1;

[0606] (c) Module M3, which includes Akt1, Ankfy1, Apc, Arcc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbxl13, Fbxo28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, Mlst8, Mtor, Nosip, Paf1, Pik3r4, Pparg, Ppp2r2a, Ppp2r2d, Preb, Rbbp4, Rbbp5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13, S ec31a, Smad2, Syvn1, Taf5l, Traf2, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1 and Zbtb11;

[0607] (d) Module M4, which includes Cdc40, Ddx41, Plrg1, Ppil2, Ppwd1, Prpf19, Prpf4, Sart1, Smu1, Snrnp40 and Wdr70;

[0608] (e) Module M5, which includes Acaca, Ambra1, Amfr, Arih1, Cbll1, Cfap57, Cnot4, Cyld, Dcaf7, Det1, Dpf2, Eed, Efcab8, Egr2, Fasn, Fb xw7, Foxo3, Gsk3b, Hectd3, Hira, Icos, Ifnar1, Ikbke, Ints12, Junb, Kat6a, Kctd10, Kctd13, Kctd21, Kctd5, Klhl30, Klhl6, Lztr1, March6, Msl2, Nf1, Nfkb1, Nsd1, Patz1, Pias1, Prdm1, Pten, Rfwd2, Rnf139, Socs3, Spag16, Strap, Stub1, Syk, Tab1, Tank, Tbk1, Tnf, Trim45, Trip12, Ube2j2, Wdfy2, Wdr61, Wdr81, Wdr91, Zbtb25, Zfp106, Zfp91 and Zmiz2; and

[0609] (f) Module M6, which includes Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fbxw11, Fus, Gm9840, Hif1a, Huwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, Ranbp2, Rbb p6, Rbck1, Rbx1, Rc3h1, Rela, Rlim, Rnf144a, Rnf31, Rnf7, Seh1l, Skp1a, Spop, Ssr3, Tbl1xr1, Tceb1, Tceb2, Tceb3, Tdpoz5 , Thoc3, Tlr4, Traf6, Trim28, Trim33, Ube2d3, Ube2f, Ube2h, Ube2i, Ubr4, Ubr5, Vhl, Wdr20, Wdr26, Wdr33, Zbtb17 and Zbtb7b.

[0610] For example, the genetically modified isolated cells may contain (1) alterations to at least two genes in module M1 (e.g., alterations to two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in module M1); (2) alterations to at least two genes in module M2 (e.g., alterations to two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in module M2); and (3) alterations to at least two genes in module M3 (e.g., alterations to two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in module M3). (4) Changes in at least two genes in module M4 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten or more genes in module M4); (5) Changes in at least two genes in module M5 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten or more genes in module M5); or (6) Changes in at least two genes in module M6 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten or more genes in module M6).

[0611] In some respects, the genetically modified isolated cells contain alterations to at least two genes in the first module and one or more genes in the second module, for example, alterations to at least two genes in the genes of module M1 and at least one gene in the genes of any of modules M2 to M6.

[0612] In some respects, the genetically modified isolated cells contain alterations to at least two genes in the first module and at least two genes in the second module, for example, alterations to at least two genes in the genes of module M1 and at least two genes in the genes of any of modules M2 to M6.

[0613] On the other hand, this disclosure provides a genetically modified isolated cell comprising alterations to at least two genes from one or more of the following gene sets:

[0614] (a) Gene set 1, which includes Aamp, Actb, Alcam, Ambra1, Anxa2, Aprt, Atp5e, B2m, Btf3, Ccdc88a, Cdh1, Chd4, Cirh1a, Cox4i1, Cox7a2l, Crebbp, Ctsb, Dcaf13, Ddx41, Eef1a1, Eef1b2, Eef1g, Eef2, Eif1, Eif3e, Eif3f, Eif3i, Eif3k, Fau, Gapdh, H2-D1, H2-K1, H2-M2, Hsp90ab1, Hspa 5. Hspa8, Il1rn, Laptm5, Lhfpl2, March6, Ms4a7, Mtor, Myc, Naca, Ncl, Nf1, Nol10, Npm1, Ogt, Pabpc1, Paf1, Plrg1, Pparg, Psap, Rac k1, Raf1, Rheb, Rpl10, Rpl10a, Rpl11, Rpl12, Rpl13, Rpl13a, Rpl14, Rpl15, Rpl17, Rpl18, Rpl18a, Rpl19, Rpl21, Rpl22, Rpl22l1, Rp l23, Rpl23a, Rpl24, Rpl26, Rpl27a, Rpl28, Rpl29, Rpl3, Rpl30, Rpl31, Rpl32, Rpl34, Rpl35, Rpl35a, Rpl36, Rpl36a, Rpl37, Rpl37a, Rpl38, Rpl39, Rpl4, Rpl41, Rpl5, Rpl6, Rpl7, Rpl7a, Rpl8, Rpl9, Rplp0, Rplp1, Rplp2, Rps10, Rps11, Rps12, Rps13, Rps14, Rps15, Rp s15a, Rps16, Rps17, Rps18, Rps19, Rps2, Rps20, Rps21, Rps23, Rps24, Rps25, Rps26, Rps27, Rps27a, Rps28, Rps29, Rps3, Rps3a1, Rps 4x, Rps5, Rps6, Rps7, Rps8, Rps9, Rpsa, Rptor, Sgk1, Ssr4, Tab1, Taf5, Tpt1, Uhrf1, Uqcrh, Utp15, Wdr3, Wdr36, Wdr43, Wdr5 and Zbtb25;

[0615] (b) Gene set 2, which includes AI314180, Abcc1, Acod1, Akr1a1, Alas1, Alox5ap, Ampd3, Arih1, Ass1, B430306N03Rik, Bach1, Blvrb, Bmi1, Brca1, Btbd1, Btg1, Cat, Ccr5, Cd36, Cd52, Cd53, Cd81, Chd4, Chpf2, Clec4n, Crebbp, Creg1, Cul3, Cx cl3, Cyb5a, Dap, Dars, Dck, Ddb1, Ddit3, Egr2, Eif3f, Eif3i, Ep300, Esd, Fbxl5, Fbxw11, Gbe1, Gclm, Gdap10, G m9840, Gss, Gstm1, H3f3b, Hmox1, Hvcn1, Il1f9, Inhba, Keap1, Lipa, Lmo4, Map3k7, Mcl1, Mcoln2, Met, Mgst2, Mm p12, Mmp19, Mmp8, Mylip, Nampt, Nedd8, Nf1, Npy, Nrp1, Nup43, Nupr1, Paf1, Pf4, Pgd, Phlda1, Pla2g7, Plet1, P pfibp2, Prdx1, Prdx6, Preb, Prkcb, Procr, Ptgr1, Ptpn1, Raf1, Rbx1, Rhob, Rnasel, Rnf128, Runx2, Sdc4, Sec13 , Seh1l, Skp1a, Slc43a2, Slc48a1, Slc7a11, Slpi, Smad2, Srxn1, Taldo1, Tarm1, Thbs1, Tlr2, Tlr4, Tma16, Tpm 4. Traf2, Traf5, Traf6, Trip12, Tubb2a, Txnrd1, Ube2d3, Ube2n, Ubr5, Uchl1, Upf1, Wdr43, Wdr61, Zbtb17 and Zyx;

[0616] (c) Gene set 3, which includes Acp5, Ankfy1, Arpc1b, Atp6v0d2, Bptf, Brap, C5ar1, Ccdc88a, Cd14, Cd36, Cd63, Cebpb, Chd4, Clec4d, Clec5a, Cpd, Creg1, Ctsb, Ctsz, Cul3, Ddhd1, Dnmt3a, Egr2, Emb, and F6300. 28O10Rik, Fabp5, Fam46c, Fbxo42, Fcgr2b, Fn1, Foxo3, Fpr1, Ftl1, Gadd45a, Glrx, Gpnmb, Gp r84, Huwe1, Icam1, Id1, Il1f9, Kctd10, Keap1, Klhl6, Lcn2, Lgals1, Lgals3, Lgmn, Lipa, Lpca t2, Ly6c2, March6, Metrnl, Mgll, Mt1, Mtor, Myof, Naaa, Naca, Nf1, Paf1, Phlda1, Pid1, Pik3 r4, Pld3, Plet1, Plk2, Pou2f2, Pparg, Prdx5, Psap, Ptpn11, Rab3il1, Rela, Rfwd2, Rnase2a, S 100a1, S100a11, S100a8, Saa3, Sdc3, Serpinb2, Slamf7, Snx18, Sod2, Spata13, Stap1, Strap, Tab1, Tceb2, Tgfbi, Thbs1, Trem1, Upf1, Upp1, Vat1, Wdfy3, Wfdc21, 2010005H15Rik and Zbtb25;

[0617] (d) Gene set 4, which includes AC160336.1, Actb, Actg1, Ankfy1, Arhgdib, Bptf, Brap, Bri3, Ccr2, Ccr5, Cd274, Cdkn1a, Cfl1, Chd4, Clec4a2, Copa, Coro1a, Cotl1, Crip1, Cul1, Cul3, Dars, Ddhd1, Ddit3, Ear2, Eif3f, Eif3i, Ep300, Fbxw11, Flna, Gbp2, Gbp5, Grb2, Gtf3c1, H2-D1, H2-K1, Huwe1, If i27l2a, Il1rn, Keap1, Klk1b1, Lcp1, Lgals1, Lpl, Lrr1, Lsp1, Malat1, Marcksl1, Med8, Mgll, Mndal, Mtor, Naca, Nedd8, Nf1, Paf1, Pfn1, Pi k3r4, Pten, Ptma, Ptpn11, Rack1, Rela, Rnf20, Sdc4, Skp1a, Taf3, Taf5, Tlr4, Tmsb4x, Ubb, Ube2i, Upf1, Vhl, Wdfy3, Wdr43, Wdr82 and Wfdc17;

[0618] (e) Gene set 5, which includes AA467197, AW112010, Abcg1, Acod1, Bcl2a1b, Bcl2a1d, Cav1, Ccl17, Ccl3, Ccl4, Cd14, Cd200r1, Cd300lf, Cdkn1a, Cebpb, Cflar, Chd4, Clec4e, Clic4, Copa, Cpd, Cpeb4, Cul1, Cul3, Cx cl1, Cxcl2, Cxcl3, Ehd1, Ep300, Fam102b, Fam20c, Fbxw11, Gda, Gpr84, Hist1h1c, Hivep3, Ikbke, I kbkg, Il12b, Il1a, Il1b, Il6, Ing3, Inhba, Kctd21, Klf4, Laptm5, Mafb, Malat1, Malt1, Marcks, Ma rcksl1, Marco, Met, Mtpn, Nabp1, Nedd8, Nfkb1, Nfkbiz, Nlrp3, Nrp2, Nup62, Ogt, Paf1, Plek, Plrg 1. Ppfia3, Prpf19, Ptgs2, Ptx3, Rassf4, Rbx1, Rela, Rfwd2, Rnf31, Serpinb2, Sh3bp5, Skp1a, Slc7 a11, Slc7a2, Slco3a1, Slfn2, Smad2, Smu1, Socs6, Sod2, Spop, Stub1, Tank, Tbk1, Tceb3, Tlr4, Tnf , Tnfaip3, Tnfsf15, Tradd, Traf6, Trip12, Txnip, Ube2d3, Ube2i, Ube2n, Wdr82, Zbtb17 and Zc3h12c;

[0619] (f) Gene set 6, which includes AA467197, Ahr, Akt1, Ankfy1, Axl, Bhlhe40, Bhlhe41, Btg1, Ccl17, Ccl22, Ccr2, Cd40, Cd52, Cd74, Cebpb, Chd4, Clec4e, Clec4n, Clic4, Cst3, Cstf1, Ctsb, Ctsd, Cxcl16. Dcstamp, Egr2, Etv3, Fabp4, Fabp5, Fam20c, Fbxw7, Fbxw9, Foxo3, Fpr1, Fth1, Ftl1, Gbp2, G bp5, Gm2a, Gnb1, Gnb2, Grb2, Grk3, Gsk3b, H2-Aa, H2-Ab1, Hmox1, Igf1, Il4i1, Irf4, Itgax, J ak2, Jund, Kcmf1, Klhl6, Kmt2d, Lgals1, Lyz2, March6, Mgl2, Mmp12, Mtor, Myc, Ndufa4, Nec tin2, Nf1, Nfkb1, Pfkp, Pid1, Pik3r4, Plet1, Pmp22, Pten, Ptpn1, Ptpn11, Rheb, Rilpl2, Rp tor, S100a8, Sart1, Scimp, Sdcbp, Sema4a, Sgk1, Slamf9, Smad2, Srgn, Stat5a, Tab1, Taf5l , Tank, Tceb1, Tceb2, Tlr2, Tlr4, Traf2, Traf3, Ube2n, Vcan, Wdfy3, Wdr26, Wdr61 and Zfp36l1;

[0620] (g) Gene set 7, which includes Abca1, Actb, Ambra1, Atf4, Atp5g1, Atp5j, Atp5j2, Bcl2a1b, Calm1, Cfl1, Chd4, Copa, Copb2, Cotl1, Cox8a, Cul3, Cybb, Dbi, Ddit3, Eef1a1, Eif3f, Eif3i, Fbxo28, Fcer1g, Gpx1, Grb2, H2-M2, H2afz, H3f3a, Il1rn, Inhb a, Keap1, Kmt2d, Lhfpl2, Ly6e, March6, Med8, Mtor, Nedd8, Nf1, Nme1, Ogt, Paf1, Plrg1, Pnp, Pparg, Rack1, S100a10 , S100a4, S100a6, Sdc4, Sec13, Serf2, Sgk1, Smad2, Smu1, Sqstm1, Tab1, Taf3, Trp53, Uhrf1, Wdr43, Wdr61 and Zbtb25;

[0621] (h) Gene set 8, which includes Aamp, Acsl1, Ambra1, Arf4, Arih2, Atf4, Bop1, C1qb, Calr, Canx, Ccng1, Cdkn1a, Chd4, Cirh1a, Clec2d, Copa, Copb2, Cope, Cpd, Ctss, Cul3, Dad1, Dap, Dcaf13, Ddit3, Ddx41, Dstn, Eif 3f, Eif3i, Erp29, Fbxw7, Fth1, Ftl1, Gm9840, Grb2, Gtf3c1, Herpud1, Hif1a, Hnrnpa3, Hsp90b1, Hs pa5, Ift20, Keap1, Kmt2d, Krtcap2, Lgals3, Lrr1, Lyz2, Manf, Map3k7, Mthfd2, Mtor, Myc, Naca, Ne dd8, Nf1, Nol10, Ostc, P4hb, Pdia3, Pdia4, Pdia6, Phgdh, Plrg1, Preb, Prpf19, Pten, Ptpn1, Rack1 , Rbx1, Rela, Rpl22l1, Rpn1, Rps19, Rrp9, Sdf2l1, Sec11c, Sec13, Sec22b, Sec31a, Sec61b, Sec61g , Selenos, Serf2, Serp1, Sf3b5, Spcs2, Ssr3, Surf4, Syvn1, Tceal9, Tceb1, Tceb2, Timm13, Tpt1, T ram1, Trp53, Ube2f, Ufm1, Uqcrq, Utp15, Vcp, Vhl, Vprbp, Wdr36, Wdr43, Wdr5, Wdr74, Wdr75 and Xbp1;

[0622] (i) Gene set 9, which includes Acod1, Adam8, Atp5g3, Brap, C3ar1, Ccl2, Ccl3, Ccl4, Ccl7, Ccnd1, Cd300ld, Cd63, Ch25h, Chd4, Chil3, Crip1, Ctsb, Ctsl, Cul1, Cul3, Cxcl1, Cyp51, Det1, Ear2, Egr2, F10, Fbxo42, F bxw11, Ffar2, Fpr2, Fyb, Gas7, Gm9840, Gnb2, Gpnmb, Grb2, Gsk3b, Hmgcs1, Huwe1, Ifitm3, Il1f9, Itgam, Jun, Kctd12, Kctd5, Keap1, Klhdc4, Kmt2c, Kmt2d, Lgals1, Lgals3, Lmna, Lmo4, Lrpap1, Ly6 c2, Lztr1, Maf, March6, Mcemp1, Mmp12, Mmp13, Mmp8, Msr1, Mtor, Naaa, Naca, Nf1, Nfkbiz, Npc2, N py, Paf1, Pdpn, Pf4, Plet1, Pparg, Prkcd, Pten, Ptgs2, Ptpn1, Ptpn11, Ptprc, Ptx3, Rbbp5, Rela, R fwd2, Rheb, Rptor, S100a6, Saa3, Scap, Scd2, Serpinb2, Serpinb6a, Sgk1, Slc7a11, Smad2, Srgn, Syk, Syngr1, Timp2, Trem2, Ube2h, Ube2i, Ucp2, Vasp, Vhl, Wdr26, Wfdc21, Ybx1, Zbtb7a and Zfp36l2;

[0623] (j) Gene set 10, which includes Acaca, Ak4, Aldoa, Aldoc, Anapc13, Anxa2, Arih2, Arnt, Basp1, Bnip3l, Bsg, C3ar1, Ccl9, Cd52, Chil3, Copa, Cul2, Cul3, Cul5, Egr2, Eif3i, Eif4ebp1, Emilin2, Eno1, Ep300, Fam162a, Gapdh, Gbe1, Gpi1, Gsn, Herpud1, Hif1a, Higd1a, Hilpda, Hk1, Hk2, Hmox1, Huwe1, Ier3, Kctd10, Klk1b1, Ldha, Lgals3, Lipa, Lmo4, Lpcat2, L yz2, March6, Mif, Mt1, Mt2, Mtor, Myc, Ndufv3, Nf1, Pdk1, Pfkl, Pgam1, Pgk1, Pgm2, P km, Prdx1, Prelid1, Ptpn1, Ptpn11, Rbpj, Rfwd2, Rilpl2, Rnase2a, Sacs, Scd2, Sdc3, Sdc4, Sec13, Slamf9, Slc16a3, Slc2a1, Slc7a2, Smu1, Socs3, Strap, Tarm1, Tceb1, T ceb2, Tgm2, Tlr4, Tpi1, Trf, Ube2f, Vhl, Vim, Wdr43, Wdr82, Wfdc17 and 2010005H15Rik;

[0624] (k) Gene set 11, which includes AA467197, Apobec1, Apoe, C1qa, C1qb, C1qc, C3, Car4, Ccl22, Ccl3, Ccl4, Ccl6, Ccl9, Cd83, Cdc40, Cebpb, Ch25h, Chd4, Copa, Crebbp, Cul1, Ddhd1, Ddx41, Egr2, Eif3f, Eif3i, Ep300, Fam49a, Fbxw11, Fn1, Fnbp1l, Gadd45b, Hdac4, Icam1, Icosl, Id2, Ikbkg, Il1a, Il4i1, Inhba, Itgax, Itgb2, Kctd10, Klk1b11, Lpl, Maf, Marks, Marksl1, M ed8, Met, Mmp12, Ms4a6c, Ms4a7, Mt2, Mycbp2, Naca, Nedd8, Nfkbia, Phlda1, Plaur, Plrg1, Pparg, Ppfibp2, Prpf19, Ptpn1, Rassf4, Rfwd2, Ring1, Rnase2a, Rpl12, Scimp, Sec13 ,Skp1a,Slc43a2,Smu1,Sqstm1,Syk,Syvn1,Taf5l,Tceb2,Tmem176a,Tmem176b,Tnfaip 2. Traf3, Ufm1, Upp1, Wdr5, Wdr70, Wdr82, Wfdc17, Wfdc21, 0610012G03Rik, Zbtb7a and Zyx;

[0625] (l) Gene set 12, which includes Ambra1, Aplop2, Atp5g1, Atpif1, B2m, Ccdc88a, Chd4, Copa, Cyba, Ddit3, Ear2, Egr2, Eif3f, Eif3i, Eif5, Fcgrt, Grn, H2-M2, H2-Q6, Hint1, Id1, Ifi204, Itgal, Kctd12, Laptm5, Lgals3, Ly6e, Mgst1, Mpeg1, Mtdh, Nf1 Nfe2l2, Nupr1, Paf1, Pparg, Prpf19, Psmb5, Psmb6, Pycard, Rack1, Rnase4, Rpl22l1, Rpl37a, Rplp0, Sart1, Sdc3, S ec61b, Smad2, Smdt1, Smu1, Spp1, Syvn1, Tab1, Taf5, Taf5l, Tagln2, Tmsb10, Traf2, Traf3, Trf, Trp53, Upf1 and Wdr5;

[0626] (m) Gene set 13, which includes Ankfy1, Anxa1, Anxa5, Aph1c, Brap, C3ar1, Ccnd2, Ccr1, Cd300lf, Cd38, Cd68, Cd9, Cdc27, Cdc40, Cebpb, Chd4, Chst11, Clec4e, Creb5, Cul1, Cul3, Cxcl3, Cyba, Dstn, Eif3f, Eif3i, Emp1, Epha4, Fam102b, Fam46a, Fbxw11, Fn1, Foxo3, Ftl1, Furin, Gas7, Gdf15, Grb2, H2-K1, Huwe1, Icam1, Il7r, Inhba, Keap1, Klhdc4, Klk1b11, Lgal s3, Lpl, Ly6c2, Lyz2, March6, Mbnl1, Mmp14, Mmp8, Ms4a7, Naca, Neat1, Nf1, Nrp2, Pli n2, Plk2, Plrg1, Polr2l, Prdx1, Pten, Ptpn1, Rack1, Rasgef1b, Rasgrp1, Rela, Rnf20, Rnh1, Rpl22l1, Rrp9, Saa3, Scd2, Sdc4, Sec13, Selenoh, Serp1, Skp1a, Slamf7, Slc7a2 , Smu1, Spp1, Tab1, Taf5, Ube2d3, Ubr4, Upf1, Vim, Wdr43, Wdr5, Wdr70, Wdr82 and Zbtb25;

[0627] (n) Gene set 14, which includes AC160336.1, Adgre1, Adgre4, Adgrl2, Anxa1, B2m, C1qb, C3, Car4, Ccdc88a, Ccl6, Cd52, Cdc40, Chd4, Chil3, Crip1, Ctsk, Ddx41, Dpf2, Egr2, Eif3i, Ep300, F7, Fcer1g, Fn1, Foxo3, Gpx3, H2-D1, H2-K1, H2-Q6, H2-Q7, H3f3b, Hira, Hsp90aa1, Hvcn1, Id2, Ifi203, Il18, Il1f9, Kdm5c, Klhl6, Lgals1, Lgals3, Ly6e, Malt1, March6, Marks. Mcub, Med8, Mpc1, Ms4a6d, Msrb1, Mt1, Mt2, Nedd8, Nfe2l2, Nov, Npc2, Paf1, Pdzk1ip1, Phgdh, Pias1, Pla2g7, Plrg1, Ppic, Ppil2, Ppwd1, Prkcd, Prpf19, Ptges, Rab32, Rbx1, and

[0628] (o) Gene set 15, which includes AC160336.1, Adgre1, Ahnak, Alcam, Aprt, Bcl2l11, Blvrb, Brap, Bub3, C1qb, C1qc, C3ar1, Cd300c2, Cd33, Cd68, Cdc40, Cebpb, Chchd2, Clec12a, Clec4n, Copa, Csf1r, Ctsz, Cul3, Cul5, Cyba, Ddx41, Dstn, Egr2, Ep300, F7, Fbxw7, Fcer1g, Fcgr2b, Gmfg, Gngt2, Gpr84, Hsp90aa1, Huwe1, Igf1, Kat6a, Kctd12b, Kdm5c, Keap1, Kmt2d, Ls t1, Mmp14, Mpeg1, Myc, Naca, P2ry14, Paf1, Pirb, Plrg1, Pou2f2, Pparg, Ppil2, Ppwd1 , Prkcd, Prpf19, Prpf4, Ptpn1, Ptpn18, Rack1, Rbbp5, Rnf20, Rnf40, Rnf7, Rps27l, Sat 1. Serpinb2, Smu1, Socs3, Spp1, Taf5, Tank, Tceb1, Tceb2, Tgm2, Tnfsf15, Traf2, Tre m2, Tyrobp, Ufm1, Vcan, Wdr1, Wdr33, Wdr43, Wdr5, Wdr61, Wdr70, Wdr82, Wfdc21 and Ybx1.

[0629] For example, genetically modified isolated cells may contain (1) alterations to at least two genes in gene set 1 (e.g., alterations to two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 1); (2) alterations to at least two genes in gene set 2 (e.g., alterations to two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 2); (3) alterations to at least two genes in gene set 3 (e.g., alterations to two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 3); (4) alterations to gene set 4 (5) At least two genes in gene set 4 are altered (e.g., two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 4 are altered); (6) At least two genes in gene set 6 are altered (e.g., two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 5 are altered); (7) At least two genes in gene set 7 are altered (e.g., at least two genes in gene set 7 are altered); (8) At least two genes in gene set 7 are altered (e.g., two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 5 ...9) At least two genes in gene set 7 are altered (e.g., two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 6 are altered); (10) At least two genes in gene set 7 are altered (e.g., two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 7 are altered); (11) At least two genes in gene set 7 are altered (e.g., two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 7 are altered); (12) At least two genes in gene set 7 are altered (e.g., two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 7 are altered); (13) At least two genes in gene set 7 are altered (e.g., two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 7 (8) Changes in at least two genes in gene set 8 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 8); (9) Changes in at least two genes in gene set 9 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 9); (10) Changes in at least two genes in gene set 10 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more genes in gene set 10). (11) Changes in at least two genes in gene set 11 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 11); (12) Changes in at least two genes in gene set 12 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 12); (13) Changes in at least two genes in gene set 13 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 13).(14) Changes in at least two genes in gene set 14 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 14); or (15) Changes in at least two genes in gene set 15 (e.g., changes in two, three, four, five, six, seven, eight, nine, ten, or more than ten genes in gene set 15).

[0630] In some respects, the genetically modified isolated cells contain alterations to at least two genes in a first gene set and one or more genes in a second gene set, for example, alterations to at least two genes in gene set 1 and at least one gene in any of gene sets 2 to 15.

[0631] In some respects, the genetically modified isolated cells contain alterations to at least two genes in the first module and at least two genes in the second module, for example, alterations to at least two genes in gene set 1 and at least two genes in any of gene sets 2 to 15.

[0632] The alteration can be a loss-of-function mutation (e.g., a mutation that results in a decrease or elimination of protein function, including deletion) or a gain-of-function mutation (e.g., a mutation that results in an increase in gene function, including overexpression and gene duplication). For example, a cell containing alterations to two genes in module M1 may contain loss-of-function mutations in both genes; may contain gain-of-function mutations in both genes; or may contain a loss-of-function mutation in the first gene and a gain-of-function mutation in the second gene. In some aspects, at least one of the alterations is a loss-of-function alteration. In some aspects, at least one of the alterations is a gain-of-function alteration.

[0633] In some respects, the genetically modified isolated cells are dendritic cells, macrophages, T cells, TILs, or NK cells. In some respects, the genetically modified isolated cells are used in cell therapies as described above, such as dendritic cell therapy, macrophage therapy, ACT, TIL therapy, engineered TCR therapy, CAR-T therapy, CAR-Treg therapy, monocyte or bone marrow cell therapy, NK cell therapy, or therapies for regenerative medicine (e.g., Müller glial cell therapy or retinal ganglion cell (RGC) therapy). In some respects, cell therapy is used to treat cancer, inflammatory diseases, or autoimmune diseases.

[0634] IX. Pharmaceutical compositions, formulations, and kits

[0635] Any modifier or agent described herein may be used in pharmaceutical compositions and formulations. Pharmaceutical compositions and formulations of modifiers or agents may be prepared by mixing one, two, three, four, or more agents of desired purity with one or more optional pharmaceutical carriers (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. editor (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutical carriers are generally non-toxic to the treated individual at the doses and concentrations used, and include, but are not limited to: buffers, such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl diammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); low molecular weight (less than about 10 residues). Polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc protein complexes); and / or nonionic surfactants, such as polyethylene glycol (PEG). Exemplary pharmaceutical carriers also include interstitial drug dispersants such as soluble neutral active hyaluronidase glycoprotein (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoprotein, such as rHuPH20 (…). Baxter International, Inc. Certain exemplary sHASEGPs and methods of use (including rHuPH20) are described in U.S. Patent Publications 2005 / 0260186 and 2006 / 0104968. In one aspect, sHASEGP is combined with one or more additional glycosaminoglycans, such as chondroitinase.

[0636] The formulations described herein may also contain more than one active ingredient essential for the specific indication being treated, preferably active ingredients having complementary activities that do not adversely affect each other. For example, it may be desirable to provide additional therapeutic agents. Such active ingredients are appropriately present in a combination at amounts effective for the intended purpose.

[0637] The active ingredient can be encapsulated in microcapsules (e.g., hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules) prepared by, for example, cohesive techniques or interfacial polymerization; encapsulated in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules); or encapsulated in crude emulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (1980).

[0638] Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing pharmaceutical agents or modifiers, in the form of molded articles, such as membranes or microcapsules. Formulations intended for in vivo administration are typically sterile. For example, sterility can be readily achieved through filtration using sterile filter membranes.

[0639] In some cases where the kit contains more than one drug or regulator, the drugs or regulators are in the same container or separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. Containers can be formed from a variety of materials, such as glass, plastics (e.g., polyvinyl chloride or polyolefins), or metal alloys (e.g., stainless steel or Hastelloy). In some cases, the container holds the formulation, and a label on or associated with the container may indicate instructions for use. The product or kit may also include other materials desired from a commercial and user perspective, including additional buffers, diluents, filters, needles, syringes, and packaging inserts with instructions for use. In some cases, the product further includes one or more other drugs. Suitable containers for one or more drugs include, for example, bottles, vials, bags, and syringes.

[0640] Any pharmaceutical preparation or modifier described herein may be included in a product or kit. Any product or kit may include instructions for administering the pharmaceutical preparation or modifier to a subject according to any of the methods described herein.

[0641] In some aspects, this disclosure features a kit comprising a modulator of the interaction between (a) one, two, or all three of Ldb2, Rnf165, and Traf2 and (b) CCR7, the kit being used to treat an individual with cancer, an inflammatory disease, or an autoimmune disease according to the methods provided in Part V of this document. In some aspects, the kit includes a packaging insert containing instructions for administering the modulator to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0642] In some aspects, this disclosure features a kit comprising: (a) an agent that reduces the expression and / or activity of Cebpb; (b) an agent that reduces the expression and / or activity of Traf2; and / or (c) an agent that increases the expression and / or activity of Dido1, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease according to the methods provided in Part VI of this document. In some aspects, the kit includes a packaging insert containing instructions for administering the agent to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

[0643] In some aspects, this disclosure features a kit comprising: (a) an agent that increases the expression and / or activity of Cebpb; (b) an agent that increases the expression and / or activity of Traf2; and / or (c) an agent that decreases the expression and / or activity of Dido1, the kit being used to treat an individual suffering from an inflammatory disease or an autoimmune disease according to the methods provided in Part VI of this document. In some aspects, the kit includes a packaging insert containing instructions for administering the agent to an individual suffering from an inflammatory disease or an autoimmune disease.

[0644] In some aspects, this disclosure features a kit comprising a modulator of the interaction between (a) Fbxw11 and (b) Nfkb1 or Nfkb2, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease according to the methods provided in Part VII of this document. In some aspects, the kit includes a packaging insert containing instructions for administering the modulator to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

[0645] In some aspects, this disclosure features a kit comprising a cell therapy comprising cells containing alterations to at least two genes from one or more of the following cofunctional gene modules provided in Part VIII of this document, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease according to the methods provided in Part VII of this document. In some aspects, the kit includes a packaging insert containing instructions for administering the agent to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

[0646] In some aspects, this disclosure features a kit comprising a cell therapy comprising cells containing alterations to at least two genes from one or more of the gene sets provided in Part VIII of this document, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease according to the methods provided in Part VIII of this document. In some aspects, the kit includes a packaging insert containing instructions for administering the agent to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

[0647] In some aspects, this disclosure features a kit comprising a modulator of the interaction between Rfwd2 and one or more of Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5, for use in treating an individual with cancer, an inflammatory disease, or an autoimmune disease according to the methods provided in Part III(C) of this document. In some aspects, the kit includes a packaging insert containing instructions for administering the modulator to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0648] In some aspects, this disclosure features a kit comprising regulators of genes listed in Table 1 or Table 2, for treating individuals suffering from diseases or disorders related to APC and / or inflammation according to the methods provided in Part IV of this document. In some aspects, this disclosure features a kit comprising regulators of genes listed in Table 1, for treating individuals suffering from diseases or disorders related to APC and / or inflammation according to the methods provided in Part IV of this document. In some aspects, this disclosure features a kit comprising regulators of genes listed in Table 2, for treating individuals suffering from diseases or disorders related to APC and / or inflammation according to the methods provided in Part IV of this document. In some aspects, the kit includes a packaging insert containing instructions for administering the regulators to individuals suffering from diseases or disorders related to APC and / or inflammation.

[0649] All patents, patent publications, and references cited in this specification are incorporated herein by reference in their entirety.

[0650] X. Example

[0651] Example 1. Systematic screening of E3 ligases in immune dendritic cells

[0652] This example describes a study in which a large gene family of E3 ligases and their interacting partners are characterized by the cellular response of primary immune cells to infla...

Claims

1. A method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering to the individual an effective amount of one, two, or all three of (a) LIM domain-binding protein 2 (Ldb2), ring finger protein 165 (Rnf165), and TNF receptor-associated factor 2 (Traf2) as a modulator of the interaction between (b) chemokine receptor type 7 (CCR7).

2. The method of claim 1, wherein the individual has cancer, and the modulator is an agent that reduces the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

3. The method of claim 1, wherein the individual suffers from an inflammatory disease or an autoimmune disease, and the modulator is an agent that increases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

4. A method for increasing the expression of chemokine receptor type 7 (CCR7) in antigen-presenting cells (APCs), the method comprising contacting the APCs with an effective amount of an agent that reduces the expression and / or activity of one, two, or all three of LIM domain-binding protein 2 (Ldb2), cyclic finger protein 165 (Rnf165), and TNF receptor-associated factor 2 (Traf2).

5. The method of claim 4, wherein the APC is in an individual.

6. The method of claim 5, wherein the individual has cancer.

7. The method according to any one of claims 4 to 6, wherein the CCR7 expression in the APC is increased by at least 10% relative to the expression in the absence of the drug.

8. A method for increasing the migration of APCs to tumors and / or lymph nodes in an individual, the method comprising administering to the individual an effective amount of an agent that reduces the expression and / or activity of one, two, or all three of LIM domain-binding protein 2 (Ldb2), ring finger protein 165 (Rnf165), and TNF receptor-associated factor 2 (Traf2).

9. The method of claim 8, wherein the individual has cancer.

10. The method of claim 9, wherein the migration of APCs to the tumor and / or lymph nodes in the individual is increased by at least 10% relative to migration in the absence of the agent.

11. The method according to any one of claims 4 to 10, wherein the APC is a dendritic cell (DC), a macrophage, or a glial cell.

12. The method according to claim 11, wherein the glial cells are microglia, astrocytes, or oligodendrocytes.

13. The method of claim 11, wherein the APC is a DC.

14. A method for increasing T cell homing to a tumor in an individual, the method comprising administering to the individual an effective amount of an agent that reduces the expression and / or activity of one, two, or all three of LIM domain-binding protein 2 (Ldb2), ring finger protein 165 (Rnf165), and TNF receptor-associated factor 2 (Traf2).

15. The method of claim 14, wherein T cell homing to the tumor in the individual is increased by at least 10% relative to T cell homing in the absence of the agent.

16. The method according to claim 1 or 3, wherein the inflammatory disease or autoimmune disease is a neurodegenerative disease, arthritis, allergic reaction, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease.

17. The method of claim 16, wherein the neurodegenerative disease is multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD).

18. The method of claim 16, wherein the inflammatory disease or autoimmune disease is Crohn's disease.

19. The method according to any one of claims 2 to 18, wherein the agent is a protein hydrolysis targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or an inhibitory nucleic acid.

20. The method of claim 19, wherein the inhibitory nucleic acid is ASO or siRNA.

21. The method of claim 19, wherein the antigen-binding fragment is a double-Fab fragment. Fv, Fab, Fab'-SH, F(ab')2, bisomatic antibody, linear antibody, scFv, scFab, VH domain or VHH domain.

22. The method of claim 19 or 21, wherein the antibody or its antigen-binding fragment binds to Ldb2, Rnf165 or Traf2.

23. The method of claim 19 or 21, wherein the antibody or its antigen-binding fragment binds to CCR7.

24. The method according to any one of claims 19 and 21 to 23, wherein the agent is a bispecific antibody comprising an antigen-binding domain targeting the tumor microenvironment.

25. The method according to any one of claims 1 to 24, wherein the method further comprises administering one or more additional agents to the individual or contacting the APC with one or more additional agents.

26. The method according to any one of claims 1 to 25, wherein the method further comprises administering one or more agents to the individual or contacting the APC with one or more agents, the one or more agents regulating Akt1, Ankfy1, Apc, Arcc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbxl13, Fbxo28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, M Expressions of one or more of the following: apk14, Med8, Mlst8, Mtor, Nosip, Paf1, Pik3r4, Pparg, Ppp2r2a, Ppp2r2d, Preb, Rbbp4, Rbbp5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13, Sec31a, Smad2, Syvn1, Taf5l, Traf2, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1, and Zbtb11.

27. A kit comprising a modulator of the interaction between (a) one, two, or all three of Ldb2, Rnf165, and Traf2 and (b) CCR7, said kit being used to treat an individual with cancer, an inflammatory disease, or an autoimmune disease by the method of any one of claims 1 to 3 and 16 to 26.

28. The kit of claim 27, wherein the kit includes a packaging insert containing instructions for administering the modulator to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

29. A method for monitoring the response of an individual with cancer, an inflammatory disease, or an autoimmune disease to treatment with a modulator of the interaction between (a) one, two, or all three of Ldb2, Rnf165, and Traf2 and (b) CCR7, said method comprising: (i) Determine the expression levels of one or more of Ldb2, Rnf165, and Traf2 in biological samples obtained from the individual at a time point following administration of the regulator; and (ii) The expression levels of one or more genes in the biological sample are compared with reference levels to monitor the individual's response to treatment with the modulator.

30. The method of claim 29, wherein the reference level is selected from the group consisting of: (i) the expression level of the one or more genes in a biological sample obtained from the individual prior to the administration of the regulator; (ii) the expression level of the one or more genes in a reference population; (iii) a pre-specified expression level for the one or more genes; or (iv) the expression level of the one or more genes in a biological sample obtained from the individual at a previous time point, wherein the previous time point is after the administration of the regulator.

31. The method of claim 29 or 30, wherein the individual has cancer, the expression level of one or more genes in the biological sample obtained from the individual is increased relative to the reference level, and the method further comprises administering one or more additional doses of the modulator to the individual, wherein the modulator is an agent that reduces the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

32. The method of claim 29 or 30, wherein the individual suffers from an inflammatory disease or an autoimmune disease, the expression level of one or more genes in the biological sample obtained from the individual is reduced relative to the reference level, and the method further comprises administering one or more additional doses of the modulator to the individual; wherein The regulator is a drug that increases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

33. A method for treating an individual with cancer, an inflammatory disease, an autoimmune disease, or an infectious disease, the method comprising administering an effective amount of: (a) Agents that reduce the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) Agents that reduce the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) Agents that increase the expression and / or activity of death-inducing termination factor 1 (Dido1).

34. The method of claim 33, wherein the autoimmune disease is associated with a reduced proportion of migratory dendritic cells (mDCs).

35. The method of claim 34, wherein the individual has a loss-of-function mutation in Dido1.

36. A method for treating an individual with an inflammatory disease, an autoimmune disease, or an infectious disease, the method comprising administering an effective amount of: (a) Agents that increase the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) Agents that increase the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) Agents that reduce the expression and / or activity of Dido1 (death-inducing termination factor 1).

37. A method for increasing the proportion of migratory dendritic cells (mDCs) in an individual, the method comprising administering an effective amount of: (a) Agents that reduce the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) Agents that reduce the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) Agents that increase the expression and / or activity of death-inducing termination factor 1 (Dido1).

38. The method of claim 37, wherein the proportion is the proportion in the tumor or tissue of the individual.

39. The method of claim 37 or 38, wherein the proportion of mDC in the individual is increased by at least 10% relative to the proportion in the absence of the agent.

40. A method for increasing an individual's antitumor immunity, the method comprising administering an effective amount of: (a) Agents that reduce the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) Agents that reduce the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) Agents that increase the expression and / or activity of death-inducing termination factor 1 (Dido1).

41. The method of claim 40, wherein the individual's antitumor immunity is increased by at least 10% relative to the antitumor immunity in the absence of the agent.

42. A method for reducing the proportion of migratory dendritic cells (mDCs) in an individual, the method comprising administering an effective amount of: (a) Agents that increase the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) Agents that increase the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) Agents that reduce the expression and / or activity of Dido1 (death-inducing termination factor 1).

43. The method of claim 42, wherein the proportion is the proportion in the tumor or tissue of the individual.

44. The method of claim 42 or 43, wherein the proportion of mDC in the individual is reduced by at least 10% relative to the proportion in the absence of the agent.

45. A method for reducing the autoimmune activity of an individual, the method comprising administering an effective amount of: (a) Agents that increase the expression and / or activity of CCAAT / enhancer-binding protein β (Cebpb); (b) Agents that increase the expression and / or activity of TNF receptor-associated factor 2 (Traf2); and / or (c) Agents that reduce the expression and / or activity of Dido1 (death-inducing termination factor 1).

46. ​​The method of claim 45, wherein the individual's autoimmune activity is reduced by at least 10% relative to antitumor immunity in the absence of the agent.

47. The method according to any one of claims 33 to 36, wherein the inflammatory disease or autoimmune disease is a neurodegenerative disease, arthritis, allergic reaction, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease.

48. The method of claim 47, wherein the neurodegenerative disease is MS. AD, ALS, or PD.

49. The method according to any one of claims 33 to 48, wherein the agent is a protein hydrolysis targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or an inhibitory nucleic acid.

50. The method of claim 49, wherein the inhibitory nucleic acid is ASO or siRNA.

51. The method according to claim 49, wherein the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, a bisomatic antibody, a linear antibody, scFv, scFab, a VH domain, or a VHH domain.

52. The method according to claim 49 or 50, wherein the antibody or its antigen-binding fragment binds to Cebpb, Traf2 and / or Dido1.

53. The method according to any one of claims 33 to 52, wherein the method further comprises administering one or more additional agents to the individual.

54. The method according to any one of claims 33 to 53, wherein the method further comprises administering to the individual one or more agents that regulate the expression of one or more of the following: (a) Ago2, Ahr, Anapc13, Bach1, Baz1a, Bid, Bptf, Brca1, Brwd3, Btbd1, Cblc, Ccnf, C dc27, Cntn4, Copa, Copb2, Coro1a, Cpne9, Cul4b, Ddb1, E4f1, Ecel1, Fbxl14, Fbxl5, Fbxo11, Fbxo42, Fzr1, Gemin5, Gm10697, Gm9117, Gtf2h2, Gtf3c1, Hdac4, Hectd1, If t122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23, Klhl3, Kmt2b, LOC1008617 84. Lrr1, Lrrc41, Map3k7, Mdm4, Mib1, Mkrn1, Mnat1, Naca, Nsmaf, Ogt, Pa2g4, Pcif1 , Ppp1r11, Prc1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah2, Taf3, Tdpoz2 , Tmem183a, Tnfsf11, Tradd, Traf3ip2, Trim35, Trim7, Tssc1, Ttc3, Ube2n, Ufl1, Un kl, Upf1, Vdr, Wdhd1, Wdr48, Wdr95, Wwp1, Ybx1, Zbtb14, Zbtb49, Zbtb7a and Zmiz1; and / or (b)Akt1, Ankfy1, Apc, Arpc1b, Birc2, Bmi1, Bub3, Cacybp, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbx l13, Fbxo28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, Mlst8, Mtor, Nosip, Paf1 ,Pik3r4,Pparg,Ppp2r2a,Ppp2r2d,Preb,Rbbp4,Rbbp5,Rheb,Rictor,Rnf10,Rnf113a1,Rnf135,Rnf216,Rptor,Scap,Sec13, Sec31a, Smad2, Syvn1, Taf5l, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1 and Zbtb11.

55. A reagent kit comprising: (a) Agents that reduce the expression and / or activity of Cebpb; (b) Agents that reduce Traf2 expression and / or activity; and / or (c) Medications that increase Dido1 expression and / or activity. The kit is used to treat individuals with cancer, inflammatory diseases, or autoimmune diseases according to any one of claims 33 and 47 to 54.

56. The kit of claim 55, wherein the kit includes a packaging insert containing instructions for administering the agent to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

57. A reagent kit comprising: (a) Agents that increase the expression and / or activity of Cebpb; (b) Agents that increase the expression and / or activity of Traf2; and / or (c) Medications that reduce Dido1 expression and / or activity. The kit is used to treat individuals suffering from inflammatory diseases or autoimmune diseases according to any one of claims 34 and 47 to 54.

58. The kit of claim 57, wherein the kit includes a packaging insert containing instructions for administering the agent to an individual suffering from an inflammatory disease or an autoimmune disease.

59. A method for monitoring the response of an individual with cancer, an inflammatory disease, an autoimmune disease, or an infectious disease to treatment with: (a) Agents that reduce the expression and / or activity of Cebpb; (b) Agents that reduce Traf2 expression and / or activity; and / or (c) Medications that increase Dido1 expression and / or activity. The method includes: (i) Determine the expression levels of one or more of Cebpb, Traf2, and Dido1 in biological samples obtained from the individual at a time point following administration of the drug; and (ii) The expression levels of one or more genes in the biological sample are compared with reference levels to monitor the individual's response to treatment with the drug.

60. A method for monitoring the response of an individual with an inflammatory disease, autoimmune disease, or infectious disease to treatment with: (a) Agents that increase the expression and / or activity of Cebpb; (b) Agents that increase the expression and / or activity of Traf2; and / or (c) Medications that reduce Dido1 expression and / or activity. The method includes: (i) Determine the expression levels of one or more of Cebpb, Traf2, and Dido1 in biological samples obtained from the individual at a time point following administration of the drug; and (ii) The expression levels of one or more genes in the biological sample are compared with reference levels to monitor the individual's response to treatment with the drug.

61. The method of claim 59 or 60, wherein the reference level is selected from the group consisting of: (i) the expression level of the one or more genes in a biological sample obtained from the individual prior to the administration of the agent; (ii) the expression level of the one or more genes in a reference population; (iii) a pre-specified expression level for the one or more genes; or (iv) the expression level of the one or more genes in a biological sample obtained from the individual at a previous time point, wherein the previous time point is after the administration of the agent.

62. The method according to claim 59 or 61, wherein: (a) The expression and / or activity of Cebpb in the biological sample obtained from the individual is increased relative to the reference level; (b) The expression and / or activity of Traf2 in the biological sample obtained from the individual is increased relative to the reference level; and / or (c) Dido1 expression and / or activity in the biological sample obtained from the individual was reduced relative to the reference level. The method further includes administering one or more additional doses of the agent to the individual, wherein the agent reduces the expression and / or activity of Cebpb; reduces the expression and / or activity of Traf2; and / or increases the expression and / or activity of Dido1.

63. The method according to claim 60 or 61, wherein: (a) The expression and / or activity of Cebpb in the biological sample obtained from the individual was reduced relative to the reference level; (b) The expression and / or activity of Traf2 in the biological sample obtained from the individual is reduced relative to the reference level; and / or (c) Dido1 expression and / or activity increased relative to the reference level in the biological sample obtained from the individual. The method further includes administering one or more additional doses of the agent to the individual, wherein the agent increases the expression and / or activity of Cebpb; increases the expression and / or activity of Traf2; and / or decreases the expression and / or activity of Dido1.

64. A method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering to the individual an effective amount of a modulator of the interaction between (a) an F-box and WD repeat domain 11 (Fbxw11) and (b) nuclear factor κB subunit 1 (Nfkb1) or nuclear factor κB subunit 2 (Nfkb2).

65. The method of claim 64, wherein the individual has cancer, and the modulator is an agent that increases the expression and / or activity of Fbxw11.

66. The method of claim 64, wherein the individual suffers from an inflammatory disease or an autoimmune disease, and the modulator is an agent that reduces the expression and / or activity of Fbxw11.

67. A method for increasing the processing of Nfkb1 and / or Nfkb2 into an active form, the method comprising contacting cells capable of expressing Fbxw11 with an agent that increases the expression and / or activity of Fbxw11.

68. The method of claim 67, wherein the cells capable of expressing Fbxw11 are in an individual.

69. The method of claim 68, wherein the individual has cancer.

70. The method according to any one of claims 67 to 69, wherein the levels of Nfkb1 and / or Nfkb2 in active form are increased by at least 10% relative to the levels in the absence of the agent.

71. A method for reducing Nfkb1 and / or Nfkb2 to an active form, the method comprising contacting cells capable of expressing Fbxw11 with an agent that reduces the expression and / or activity of Fbxw11.

72. The method of claim 71, wherein the cells capable of expressing Fbxw11 are in an individual.

73. The method of claim 72, wherein the individual suffers from an inflammatory disease or an autoimmune disease.

74. The method according to any one of claims 71 to 73, wherein the levels of Nfkb1 and / or Nfkb2 in active form are reduced by at least 10% relative to the levels in the absence of the agent.

75. A method for increasing an immune response directed by Nfkb1 and / or Nfkb2 in an individual, the method comprising administering to the individual an effective amount of an agent that increases the expression and / or activity of Fbxw11.

76. The method of claim 75, wherein the individual has cancer.

77. A method for reducing an immune response directed by Nfkb1 and / or Nfkb2 in an individual, the method comprising administering to the individual an effective amount of an agent that reduces the expression and / or activity of Fbxw11.

78. The method of claim 77, wherein the individual suffers from an inflammatory disease or an autoimmune disease.

79. The method according to any one of claims 64, 66, 73, 74 and 78, wherein the inflammatory disease or autoimmune disease is a neurodegenerative disease, arthritis, allergic reaction, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis or Crohn's disease.

80. The method of claim 79, wherein the neurodegenerative disease is MS. AD, ALS, or PD.

81. The method according to any one of claims 65 to 80, wherein the agent is a protein hydrolysis targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or an inhibitory nucleic acid.

82. The method according to claim 81, wherein the inhibitory nucleic acid is ASO or siRNA.

83. The method according to claim 81, wherein the antigen-binding fragment is a double-Fab fragment. Fv, Fab, Fab'-SH, F(ab')2, bisomatic antibody, linear antibody, scFv, scFab, VH domain or VHH domain.

84. The method according to claim 81 or 83, wherein the antibody or its antigen-binding fragment binds to Fbxw11.

85. The method according to any one of claims 64 to 66, 68 to 70 and 72 to 84, wherein the method further comprises administering one or more additional agents to the individual.

86. The method according to any one of claims 64 to 66, 68 to 70, and 72 to 84, wherein the method further comprises administering to the individual one or more agents that regulate the expression of one or more of the following: (a)Acaca, Ambra1, Amfr, Arih1, Cbll1, Cfap57, Cnot4, Cyld, Dcaf7, Det1, Dpf2, Eed, Efcab8, Egr2, Fasn, Fbxw7, Foxo3, Gsk3b, Hectd3, Hira, Icos, Ifnar1, Ikbke, Ints12, Junb, Kat6a, Kctd10, Kctd13, Kctd21, Kctd5, Klhl30, K lhl6, Lztr1, March6, Msl2, Nf1, Nsd1, Patz1, Pias1, Prdm1, Pten, Rfwd2, Rnf139, Socs3, Spag16, Strap, Stub1, Syk, Tab1, Tank, Tbk1, Tnf, Trim45, Trip12, Ube2j2, Wdfy2, Wdr61, Wdr81, Wdr91, Zbtb25, Zfp106, Zfp91 and Zmiz2; and / or (b) Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fus, Gm9840, Hif1a, H uwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, Ranbp2, Rbbp6, Rbck1 , Rbx1, Rc3h1, Rela, Rlim, Rnf144a, Rnf31, Rnf7, Seh1l, Skp1a, Spop, Ssr3, Tbl1xr1, Tceb1, Tceb2, Tceb3, Tdpoz5, Tho c3, Tlr4, Traf6, Trim28, Trim33, Ube2d3, Ube2f, Ube2h, Ube2i, Ubr4, Ubr5, Vhl, Wdr20, Wdr26, Wdr33, Zbtb17 and Zbtb7b.

87. A kit comprising a modulator of the interaction between (a) Fbxw11 and (b) Nfkb1 or Nfkb2, said kit being used to treat an individual suffering from cancer, an inflammatory disease or an autoimmune disease by the method of any one of claims 64 to 66 and 79 to 86.

88. The kit of claim 87, wherein the kit includes a packaging insert containing instructions for administering the modulator to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

89. A method for monitoring the response of an individual with cancer, an inflammatory disease, or an autoimmune disease to treatment with a modulator of the interaction between (a) Fbxw11 and (b) Nfkb1 or Nfkb2, the method comprising: (i) Determine the expression level of one or both of the active forms of Nfkb1 and Nfkb2 in biological samples obtained from the individual at a time point following administration of the regulator; and (ii) The expression level of the active form of one or both of Nfkb1 and Nfkb2 in the biological sample is compared with a reference level to monitor the individual's response to treatment with the modulator.

90. The method of claim 89, wherein the reference level is selected from the group consisting of: (i) the expression levels of one or two genes in a biological sample from the individual obtained prior to administration of the regulator; (ii) the expression levels of the one or two genes in a reference population; (iii) a pre-specified expression level for the one or two genes; or (iv) The expression levels of one or both genes in biological samples obtained from the individual at a previous time point, wherein the previous time point is after the administration of the regulator.

91. The method of claim 89 or 90, wherein the individual has cancer, the expression level of the active form of one or both of Nfkb1 and Nfkb2 in the biological sample obtained from the individual is reduced relative to the reference level, and the method further comprises administering one or more additional doses of the modulator to the individual, wherein the modulator is an agent that increases the expression and / or activity of Fbxw11.

92. The method of claim 89 or 90, wherein the individual suffers from an inflammatory disease or an autoimmune disease, the expression level of the active form of one or both of Nfkb1 and Nfkb2 in the biological sample obtained from the individual is increased relative to the reference level, and the method further comprises administering to the individual one or more additional doses of the modulator, wherein the modulator is an agent that reduces the expression and / or activity of Fbxw11.

93. A method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering an effective amount of a cell therapy to the individual, the cell therapy comprising cells containing alterations to at least two genes from one or more of the following cofunctional gene modules: (a) Module M1, which includes Aamp, Bop1, Cirh1a, Dcaf13, Grb2, Myc, Nle1, Nol10, Pak1ip1, Ptpn11, Rack1, Raf1, Rrp9, Taf5, Tbl3, Uhrf1, Utp15, Utp18, Vprbp, Wdr3, Wdr36, Wdr43, Wdr5, Wdr74 and Wdr75; (b) Module M2, which includes Ago2, Ahr, Anapc13, Bach1, Baz1a, Bid, Bptf, Brca1, Brwd3, Btbd1, Cblc, Ccnf, Cdc27, Cntn4, Copa, Copb2, Coro1a, Cpne9, Cul4b, Ddb1, Dido1, E4f1, Ecel1, Fbxl14, Fbxl5, Fbxo11, Fbxo42, Fzr1, Gemin5, Gm10697, Gm9117, Gtf2h2, Gtf3c1, Hdac4, Hectd1, Ift122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23, Klhl3, Kmt2b, LOC100861784, Lrr1, Lrrc41, Map3k7, Mdm4, Mib1, Mkrn1, Mnat1, Naca, Nsmaf, Ogt, Pa2g4, Pcif1, Ppp1r11, Prc1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah2, Taf3, Tdpoz2, Tmem183a, Tnfsf11, Tradd, Traf3ip2, Trim35, Trim7, Tssc1, Ttc3, Ube2n, Ufl1, Unkl, Upf1, Vdr, Wdhd1, Wdr48, Wdr95, Wwp1, Ybx1, Zbtb14, Zbtb49, Zbtb7a and Zmiz1; (c) Module M3, which includes Akt1, Ankfy1, Apc, Arcc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbxl13, Fbxo28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, Mlst8, Mtor, Nosip, Paf1, Pik3r4, Pparg, Ppp2r2a, Ppp2r2d, Preb, Rbbp4, Rbbp5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13, S ec31a, Smad2, Syvn1, Taf5l, Traf2, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1 and Zbtb11; (d) Module M4, which includes Cdc40, Ddx41, Plrg1, Ppil2, Ppwd1, Prpf19, Prpf4, Sart1, Smu1, Snrnp40 and Wdr70; (e) Module M5, which includes Acaca, Ambra1, Amfr, Arih1, Cbll1, Cfap57, Cnot4, Cyld, Dcaf7, Det1, Dpf2, Eed, Efcab8, Egr2, Fasn, Fb xw7, Foxo3, Gsk3b, Hectd3, Hira, Icos, Ifnar1, Ikbke, Ints12, Junb, Kat6a, Kctd10, Kctd13, Kctd21, Kctd5, Klhl30, Klhl6, Lztr1, March6, Msl2, Nf1, Nfkb1, Nsd1, Patz1, Pias1, Prdm1, Pten, Rfwd2, Rnf139, Socs3, Spag16, Strap, Stub1, Syk, Tab1, Tank, Tbk1, Tnf, Trim45, Trip12, Ube2j2, Wdfy2, Wdr61, Wdr81, Wdr91, Zbtb25, Zfp106, Zfp91 and Zmiz2; and (f) Module M6, which includes Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fbxw11, Fus, Gm9840, Hif1a, Huwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, Ranbp2, Rbb p6, Rbck1, Rbx1, Rc3h1, Rela, Rlim, Rnf144a, Rnf31, Rnf7, Seh1l, Skp1a, Spop, Ssr3, Tbl1xr1, Tceb1, Tceb2, Tceb3, Tdpoz5 , Thoc3, Tlr4, Traf6, Trim28, Trim33, Ube2d3, Ube2f, Ube2h, Ube2i, Ubr4, Ubr5, Vhl, Wdr20, Wdr26, Wdr33, Zbtb17 and Zbtb7b.

94. A method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, the method comprising administering an effective amount of a cell therapy to the individual, the cell therapy comprising cells containing alterations to at least two genes from one or more of the following gene sets: (a) Gene set 1, which includes Aamp, Actb, Alcam, Ambra1, Anxa2, Aprt, Atp5e, B2m, Btf3, Ccdc88a, Cdh1, Chd4, Cirh1a, Cox4i1, Cox7a2l, Crebbp, Ctsb, Dcaf13, Ddx41, Eef1a1, Eef1b2, Eef1g, Eef2, Eif1, Eif3e, Eif3f, Eif3i, Eif3k, Fau, Gapdh, H2-D1, H2-K1, H2-M2, Hsp90ab1, Hspa 5. Hspa8, Il1rn, Laptm5, Lhfpl2, March6, Ms4a7, Mtor, Myc, Naca, Ncl, Nf1, Nol10, Npm1, Ogt, Pabpc1, Paf1, Plrg1, Pparg, Psap, Rac k1, Raf1, Rheb, Rpl10, Rpl10a, Rpl11, Rpl12, Rpl13, Rpl13a, Rpl14, Rpl15, Rpl17, Rpl18, Rpl18a, Rpl19, Rpl21, Rpl22, Rpl22l1, Rp l23, Rpl23a, Rpl24, Rpl26, Rpl27a, Rpl28, Rpl29, Rpl3, Rpl30, Rpl31, Rpl32, Rpl34, Rpl35, Rpl35a, Rpl36, Rpl36a, Rpl37, Rpl37a, Rpl38, Rpl39, Rpl4, Rpl41, Rpl5, Rpl6, Rpl7, Rpl7a, Rpl8, Rpl9, Rplp0, Rplp1, Rplp2, Rps10, Rps11, Rps12, Rps13, Rps14, Rps15, Rp s15a, Rps16, Rps17, Rps18, Rps19, Rps2, Rps20, Rps21, Rps23, Rps24, Rps25, Rps26, Rps27, Rps27a, Rps28, Rps29, Rps3, Rps3a1, Rps 4x, Rps5, Rps6, Rps7, Rps8, Rps9, Rpsa, Rptor, Sgk1, Ssr4, Tab1, Taf5, Tpt1, Uhrf1, Uqcrh, Utp15, Wdr3, Wdr36, Wdr43, Wdr5 and Zbtb25;(b) Gene set 2, which includes AI314180, Abcc1, Acod1, Akr1a1, Alas1, Alox5ap, Ampd3, Arih1, Ass1, B430306N03Rik, Bach1, Blvrb, Bmi1, Brca1, Btbd1, Btg1, Cat, Ccr5, Cd36, Cd52, Cd53, Cd81, Chd4, Chpf2, Clec4n, Crebbp, Creg1, Cul3, Cx cl3, Cyb5a, Dap, Dars, Dck, Ddb1, Ddit3, Egr2, Eif3f, Eif3i, Ep300, Esd, Fbxl5, Fbxw11, Gbe1, Gclm, Gdap10, G m9840, Gss, Gstm1, H3f3b, Hmox1, Hvcn1, Il1f9, Inhba, Keap1, Lipa, Lmo4, Map3k7, Mcl1, Mcoln2, Met, Mgst2, Mm p12, Mmp19, Mmp8, Mylip, Nampt, Nedd8, Nf1, Npy, Nrp1, Nup43, Nupr1, Paf1, Pf4, Pgd, Phlda1, Pla2g7, Plet1, P pfibp2, Prdx1, Prdx6, Preb, Prkcb, Procr, Ptgr1, Ptpn1, Raf1, Rbx1, Rhob, Rnasel, Rnf128, Runx2, Sdc4, Sec13 , Seh1l, Skp1a, Slc43a2, Slc48a1, Slc7a11, Slpi, Smad2, Srxn1, Taldo1, Tarm1, Thbs1, Tlr2, Tlr4, Tma16, Tpm 4. Traf2, Traf5, Traf6, Trip12, Tubb2a, Txnrd1, Ube2d3, Ube2n, Ubr5, Uchl1, Upf1, Wdr43, Wdr61, Zbtb17 and Zyx; (c) Gene set 3, which includes Acp5, Ankfy1, Arpc1b, Atp6v0d2, Bptf, Brap, C5ar1, Ccdc88a, Cd14, Cd36, Cd63, Cebpb, Chd4, Clec4d, Clec5a, Cpd, Creg1, Ctsb, Ctsz, Cul3, Ddhd1, Dnmt3a, Egr2, Emb, F630028O10Rik, Fabp5, Fam46c, Fbxo42, Fcgr2b, Fn1, Foxo3, Fpr1, Ftl1, Gadd45a, Glrx, G pnmb, Gpr84, Huwe1, Icam1, Id1, Il1f9, Kctd10, Keap1, Klhl6, Lcn2, Lgals1, Lgals3, Lgmn , Lipa, Lpcat2, Ly6c2, March6, Metrnl, Mgll, Mt1, Mtor, Myof, Naaa, Naca, Nf1, Paf1, Phlda1, Pid1, Pik3r4, Pld3, Plet1, Plk2, Pou2f2, Pparg, Prdx5, Psap, Ptpn11, Rab3il1, Rela, Rfwd2, Rnase2a, S100a1, S100a11, S100a8, Saa3, Sdc3, Serpinb2, Slamf7, Snx18, Sod2, Sp ata13, Stap1, Strap, Tab1, Tceb2, Tgfbi, Thbs1, Trem1, Upf1, Upp1, Vat1, Wdfy3, Wfdc21, 2010005H15Rik and Zbtb25; (d) Gene set 4, which includes AC160336.1, Actb, Actg1, Ankfy1, Arhgdib, Bptf, Brap, Bri3, Ccr2, Ccr5, Cd274, Cdkn1a, Cfl1, Chd4, Clec4a2, Copa, Coro1a, Cotl1, Crip1, Cul1, Cul3, Dars, Ddhd1, Ddit3, Ear2, Eif3f, Eif3i, Ep300, Fbxw11, Flna, Gbp2, Gbp5, Grb2, Gtf3c1, H2-D1, H2-K1, Huwe1, If i27l2a, Il1rn, Keap1, Klk1b1, Lcp1, Lgals1, Lpl, Lrr1, Lsp1, Malat1, Marcksl1, Med8, Mgll, Mndal, Mtor, Naca, Nedd8, Nf1, Paf1, Pfn1, Pi k3r4, Pten, Ptma, Ptpn11, Rack1, Rela, Rnf20, Sdc4, Skp1a, Taf3, Taf5, Tlr4, Tmsb4x, Ubb, Ube2i, Upf1, Vhl, Wdfy3, Wdr43, Wdr82 and Wfdc17; (e) Gene set 5, which includes AA467197, AW112010, Abcg1, Acod1, Bcl2a1b, Bcl2a1d, Cav1, Ccl17, Ccl3, Ccl4, Cd14, Cd200r1, Cd300lf, Cdkn1a, Cebpb, Cflar, Chd4, Clec4e, Clic4, Copa, Cpd, Cpeb4, Cul1, Cul3, Cx cl1, Cxcl2, Cxcl3, Ehd1, Ep300, Fam102b, Fam20c, Fbxw11, Gda, Gpr84, Hist1h1c, Hivep3, Ikbke, I kbkg, Il12b, Il1a, Il1b, Il6, Ing3, Inhba, Kctd21, Klf4, Laptm5, Mafb, Malat1, Malt1, Marcks, Ma rcksl1, Marco, Met, Mtpn, Nabp1, Nedd8, Nfkb1, Nfkbiz, Nlrp3, Nrp2, Nup62, Ogt, Paf1, Plek, Plrg 1. Ppfia3, Prpf19, Ptgs2, Ptx3, Rassf4, Rbx1, Rela, Rfwd2, Rnf31, Serpinb2, Sh3bp5, Skp1a, Slc7 a11, Slc7a2, Slco3a1, Slfn2, Smad2, Smu1, Socs6, Sod2, Spop, Stub1, Tank, Tbk1, Tceb3, Tlr4, Tnf , Tnfaip3, Tnfsf15, Tradd, Traf6, Trip12, Txnip, Ube2d3, Ube2i, Ube2n, Wdr82, Zbtb17 and Zc3h12c; (f) Gene set 6, which includes AA467197, Ahr, Akt1, Ankfy1, Axl, Bhlhe40, Bhlhe41, Btg1, Ccl17, Ccl22, Ccr2, Cd40, Cd52, Cd74, Cebpb, Chd4, Clec4e, Clec4n, Clic4, Cst3, Cstf1, Ctsb, Ctsd, Cxcl16. Dcstamp, Egr2, Etv3, Fabp4, Fabp5, Fam20c, Fbxw7, Fbxw9, Foxo3, Fpr1, Fth1, Ftl1, Gbp2, G bp5, Gm2a, Gnb1, Gnb2, Grb2, Grk3, Gsk3b, H2-Aa, H2-Ab1, Hmox1, Igf1, Il4i1, Irf4, Itgax, J ak2, Jund, Kcmf1, Klhl6, Kmt2d, Lgals1, Lyz2, March6, Mgl2, Mmp12, Mtor, Myc, Ndufa4, Nec tin2, Nf1, Nfkb1, Pfkp, Pid1, Pik3r4, Plet1, Pmp22, Pten, Ptpn1, Ptpn11, Rheb, Rilpl2, Rp tor, S100a8, Sart1, Scimp, Sdcbp, Sema4a, Sgk1, Slamf9, Smad2, Srgn, Stat5a, Tab1, Taf5l , Tank, Tceb1, Tceb2, Tlr2, Tlr4, Traf2, Traf3, Ube2n, Vcan, Wdfy3, Wdr26, Wdr61 and Zfp36l1; (g) Gene set 7, which includes Abca1, Actb, Ambra1, Atf4, Atp5g1, Atp5j, Atp5j2, Bcl2a1b, Calm1, Cfl1, Chd4, Copa, Copb2, Cotl1, Cox8a, Cul3, Cybb, Dbi, Ddit3, Eef1a1, Eif3f, Eif3i, Fbxo28, Fcer1g, Gpx1, Grb2, H2-M2, H2afz, H3f3a, Il1rn, Inhb a, Keap1, Kmt2d, Lhfpl2, Ly6e, March6, Med8, Mtor, Nedd8, Nf1, Nme1, Ogt, Paf1, Plrg1, Pnp, Pparg, Rack1, S100a10 , S100a4, S100a6, Sdc4, Sec13, Serf2, Sgk1, Smad2, Smu1, Sqstm1, Tab1, Taf3, Trp53, Uhrf1, Wdr43, Wdr61 and Zbtb25; (h) Gene set 8, which includes Aamp, Acsl1, Ambra1, Arf4, Arih2, Atf4, Bop1, C1qb, Calr, Canx, Ccng1, Cdkn1a, Chd4, Cirh1a, Clec2d, Copa, Copb2, Cope, Cpd, Ctss, Cul3, Dad1, Dap, Dcaf13, Ddit3, Ddx41, Dstn, Eif 3f, Eif3i, Erp29, Fbxw7, Fth1, Ftl1, Gm9840, Grb2, Gtf3c1, Herpud1, Hif1a, Hnrnpa3, Hsp90b1, Hs pa5, Ift20, Keap1, Kmt2d, Krtcap2, Lgals3, Lrr1, Lyz2, Manf, Map3k7, Mthfd2, Mtor, Myc, Naca, Ne dd8, Nf1, Nol10, Ostc, P4hb, Pdia3, Pdia4, Pdia6, Phgdh, Plrg1, Preb, Prpf19, Pten, Ptpn1, Rack1 , Rbx1, Rela, Rpl22l1, Rpn1, Rps19, Rrp9, Sdf2l1, Sec11c, Sec13, Sec22b, Sec31a, Sec61b, Sec61g , Selenos, Serf2, Serp1, Sf3b5, Spcs2, Ssr3, Surf4, Syvn1, Tceal9, Tceb1, Tceb2, Timm13, Tpt1, T ram1, Trp53, Ube2f, Ufm1, Uqcrq, Utp15, Vcp, Vhl, Vprbp, Wdr36, Wdr43, Wdr5, Wdr74, Wdr75 and Xbp1; (i) Gene set 9, which includes Acod1, Adam8, Atp5g3, Brap, C3ar1, Ccl2, Ccl3, Ccl4, Ccl7, Ccnd1, Cd300ld, Cd63, Ch25h, Chd4, Chil3, Crip1, Ctsb, Ctsl, Cul1, Cul3, Cxcl1, Cyp51, Det1, Ear2, Egr2, F10, Fbxo42, F bxw11, Ffar2, Fpr2, Fyb, Gas7, Gm9840, Gnb2, Gpnmb, Grb2, Gsk3b, Hmgcs1, Huwe1, Ifitm3, Il1f9, Itgam, Jun, Kctd12, Kctd5, Keap1, Klhdc4, Kmt2c, Kmt2d, Lgals1, Lgals3, Lmna, Lmo4, Lrpap1, Ly6 c2, Lztr1, Maf, March6, Mcemp1, Mmp12, Mmp13, Mmp8, Msr1, Mtor, Naaa, Naca, Nf1, Nfkbiz, Npc2, N py, Paf1, Pdpn, Pf4, Plet1, Pparg, Prkcd, Pten, Ptgs2, Ptpn1, Ptpn11, Ptprc, Ptx3, Rbbp5, Rela, R fwd2, Rheb, Rptor, S100a6, Saa3, Scap, Scd2, Serpinb2, Serpinb6a, Sgk1, Slc7a11, Smad2, Srgn, Syk, Syngr1, Timp2, Trem2, Ube2h, Ube2i, Ucp2, Vasp, Vhl, Wdr26, Wfdc21, Ybx1, Zbtb7a and Zfp36l2; (j) Gene set 10, which includes Acaca, Ak4, Aldoa, Aldoc, Anapc13, Anxa2, Arih2, Arnt, Basp1, Bnip3l, Bsg, C3ar1, Ccl9, Cd52, Chil3, Copa, Cul2, Cul3, Cul5, Egr2, Eif3i, Eif4ebp1, Emilin2, Eno1, Ep300, Fam162a, Gapdh, Gbe1, Gpi1, Gsn, Herpud1, Hif1a, Higd1a, Hilpda, Hk1, Hk2, Hmox1, Huwe1, Ier3, Kctd10, Klk1b1, Ldha, Lgals3, Lipa, Lmo4, Lpcat2, L yz2, March6, Mif, Mt1, Mt2, Mtor, Myc, Ndufv3, Nf1, Pdk1, Pfkl, Pgam1, Pgk1, Pgm2, P km, Prdx1, Prelid1, Ptpn1, Ptpn11, Rbpj, Rfwd2, Rilpl2, Rnase2a, Sacs, Scd2, Sdc3, Sdc4, Sec13, Slamf9, Slc16a3, Slc2a1, Slc7a2, Smu1, Socs3, Strap, Tarm1, Tceb1, T ceb2, Tgm2, Tlr4, Tpi1, Trf, Ube2f, Vhl, Vim, Wdr43, Wdr82, Wfdc17 and 2010005H15Rik; (k) Gene set 11, which includes AA467197, Apobec1, Apoe, C1qa, C1qb, C1qc, C3, Car4, Ccl22, Ccl3, Ccl4, Ccl6, Ccl9, Cd83, Cdc40, Cebpb, Ch25h, Chd4, Copa, Crebbp, Cul1, Ddhd1, Ddx41, Egr2, Eif3f, Eif3i, Ep300, Fam49a, Fbxw11, Fn1, Fnbp1l, Gadd45b, Hdac4, Icam1, Icosl, Id2, Ikbkg, Il1a, Il4i1, Inhba, Itgax, Itgb2, Kctd10, Klk1b11, Lpl, Maf, Marks, Marksl1, M ed8, Met, Mmp12, Ms4a6c, Ms4a7, Mt2, Mycbp2, Naca, Nedd8, Nfkbia, Phlda1, Plaur, Plrg1, Pparg, Ppfibp2, Prpf19, Ptpn1, Rassf4, Rfwd2, Ring1, Rnase2a, Rpl12, Scimp, Sec13 ,Skp1a,Slc43a2,Smu1,Sqstm1,Syk,Syvn1,Taf5l,Tceb2,Tmem176a,Tmem176b,Tnfaip 2. Traf3, Ufm1, Upp1, Wdr5, Wdr70, Wdr82, Wfdc17, Wfdc21, 0610012G03Rik, Zbtb7a and Zyx; (l) Gene set 12, which includes Ambra1, Aplop2, Atp5g1, Atpif1, B2m, Ccdc88a, Chd4, Copa, Cyba, Ddit3, Ear2, Egr2, Eif3f, Eif3i, Eif5, Fcgrt, Grn, H2-M2, H2-Q6, Hint1, Id1, Ifi204, Itgal, Kctd12, Laptm5, Lgals3, Ly6e, Mgst1, Mpeg1, Mtdh, Nf1 Nfe2l2, Nupr1, Paf1, Pparg, Prpf19, Psmb5, Psmb6, Pycard, Rack1, Rnase4, Rpl22l1, Rpl37a, Rplp0, Sart1, Sdc3, S ec61b, Smad2, Smdt1, Smu1, Spp1, Syvn1, Tab1, Taf5, Taf5l, Tagln2, Tmsb10, Traf2, Traf3, Trf, Trp53, Upf1 and Wdr5; (m) Gene set 13, which includes Ankfy1, Anxa1, Anxa5, Aph1c, Brap, C3ar1, Ccnd2, Ccr1, Cd300lf, Cd38, Cd68, Cd9, Cdc27, Cdc40, Cebpb, Chd4, Chst11, Clec4e, Creb5, Cul1, Cul3, Cxcl3, Cyba, Dstn, Eif3f, Eif3i, Emp1, Epha4, Fam102b, Fam46a, Fbxw11, Fn1, Foxo3, Ftl1, Furin, Gas7, Gdf15, Grb2, H2-K1, Huwe1, Icam1, Il7r, Inhba, Keap1, Klhdc4, Klk1b11, Lgal s3, Lpl, Ly6c2, Lyz2, March6, Mbnl1, Mmp14, Mmp8, Ms4a7, Naca, Neat1, Nf1, Nrp2, Pli n2, Plk2, Plrg1, Polr2l, Prdx1, Pten, Ptpn1, Rack1, Rasgef1b, Rasgrp1, Rela, Rnf20, Rnh1, Rpl22l1, Rrp9, Saa3, Scd2, Sdc4, Sec13, Selenoh, Serp1, Skp1a, Slamf7, Slc7a2 , Smu1, Spp1, Tab1, Taf5, Ube2d3, Ubr4, Upf1, Vim, Wdr43, Wdr5, Wdr70, Wdr82 and Zbtb25; (n) Gene set 14, which includes AC160336.1, Adgre1, Adgre4, Adgrl2, Anxa1, B2m, C1qb, C3, Car4, Ccdc88a, Ccl6, Cd52, Cdc40, Chd4, Chil3, Crip1, Ctsk, Ddx41, Dpf2, Egr2, Eif3i, Ep300, F7, Fcer1g, Fn1, Foxo3, Gpx3, H2-D1, H2-K1, H2-Q6, H2-Q7, H3f3b, Hira, Hsp90aa1, Hvcn1, Id2, Ifi203, Il18, Il1f9, Kdm5c, Klhl6, Lgals1, Lgals3, Ly6e, Malt1, March6, Marks. Mcub, Med8, Mpc1, Ms4a6d, Msrb1, Mt1, Mt2, Nedd8, Nfe2l2, Nov, Npc2, Paf1, Pdzk1ip1, Phgdh, Pias1, Pla2g7, Plrg1, Ppic, Ppil2, Ppwd1, Prkcd, Prpf19, Ptges, Rab32, Rbx1, and (o) Gene set 15, which includes AC160336.1, Adgre1, Ahnak, Alcam, Aprt, Bcl2l11, Blvrb, Brap, Bub3, C1qb, C1qc, C3ar1, Cd300c2, Cd33, Cd68, Cdc40, Cebpb, Chchd2, Clec12a, Clec4n, Copa, Csf1r, Ctsz, Cul3, Cul5, Cyba, Ddx41, Dstn, Egr2, Ep300, F7, Fbxw7, Fcer1g, Fcgr2b, Gmfg, Gngt2, Gpr84, Hsp90aa1, Huwe1, Igf1, Kat6a, Kctd12b, Kdm5c, Keap1, Kmt2d, Ls t1, Mmp14, Mpeg1, Myc, Naca, P2ry14, Paf1, Pirb, Plrg1, Pou2f2, Pparg, Ppil2, Ppwd1 , Prkcd, Prpf19, Prpf4, Ptpn1, Ptpn18, Rack1, Rbbp5, Rnf20, Rnf40, Rnf7, Rps27l, Sat 1. Serpinb2, Smu1, Socs3, Spp1, Taf5, Tank, Tceb1, Tceb2, Tgm2, Tnfsf15, Traf2, Tre m2, Tyrobp, Ufm1, Vcan, Wdr1, Wdr33, Wdr43, Wdr5, Wdr61, Wdr70, Wdr82, Wfdc21 and Ybx1.

95. The method according to claim 93 or 94, wherein the cell therapy is dendritic cell therapy, macrophage therapy, adoptive T-cell therapy (ACT), tumor-infiltrating lymphocyte (TIL) therapy, engineered T-cell receptor (TCR) therapy, chimeric antigen receptor T-cell (CAR-T) therapy, CAR-Treg therapy, or natural killer (NK) cell therapy.

96. A kit comprising a cell therapy comprising cells containing alterations to at least two genes of one or more of the cofunctional gene modules according to claim 93, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease as described in claim 93 or 95.

97. A kit comprising reagents for modifying cells to include alterations to at least two genes in one or more of the cofunctional gene modules according to claim 93, said kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease as described in claim 93 or 95.

98. The kit according to claim 96 or 97, wherein the kit includes a packaging insert containing instructions for administering the agent to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

99. A kit comprising a cell therapy comprising cells containing alterations to at least two genes from one or more of the genes in the gene set according to claim 94, the kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease as described in claim 94 or 95.

100. A kit comprising reagents for modifying cells to include alterations to at least two genes from one or more of the gene sets according to claim 94, said kit being used to treat an individual suffering from cancer, an inflammatory disease, or an autoimmune disease as described in claim 94 or 95.

101. The kit according to claim 99 or 100, wherein the kit includes a packaging insert containing instructions for administering the agent to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

102. A genetically modified isolated cell comprising alterations to at least two genes in one or more of the following cofunctional gene modules: (a) Module M1, which includes Aamp, Bop1, Cirh1a, Dcaf13, Grb2, Myc, Nle1, Nol10, Pak1ip1, Ptpn11, Rack1, Raf1, Rrp9, Taf5, Tbl3, Uhrf1, Utp15, Utp18, Vprbp, Wdr3, Wdr36, Wdr43, Wdr5, Wdr74 and Wdr75; (b) Module M2, which includes Ago2, Ahr, Anapc13, Bach1, Baz1a, Bid, Bptf, Brca1, Brwd3, Btbd1, Cblc, Ccnf, Cdc27, Cntn4, Copa, Copb2, Coro1a, Cpne9, Cul4b, Ddb1, Dido1, E4f1, Ecel1, Fbxl14, Fbxl5, Fbxo11, Fbxo42, Fzr1, Gemin5, Gm10697, Gm9117, Gtf2h2, Gtf3c1, Hdac4, Hectd1, Ift122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23, Klhl3, Kmt2b, LOC100861784, Lrr1, Lrrc41, Map3k7, Mdm4, Mib1, Mkrn1, Mnat1, Naca, Nsmaf, Ogt, Pa2g4, Pcif1, Ppp1r11, Prc1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah2, Taf3, Tdpoz2, Tmem183a, Tnfsf11, Tradd, Traf3ip2, Trim35, Trim7, Tssc1, Ttc3, Ube2n, Ufl1, Unkl, Upf1, Vdr, Wdhd1, Wdr48, Wdr95, Wwp1, Ybx1, Zbtb14, Zbtb49, Zbtb7a and Zmiz1; (c) Module M3, which includes Akt1, Ankfy1, Apc, Arcc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbxl13, Fbxo28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, Mlst8, Mtor, Nosip, Paf1, Pik3r4, Pparg, Ppp2r2a, Ppp2r2d, Preb, Rbbp4, Rbbp5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13, S ec31a, Smad2, Syvn1, Taf5l, Traf2, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1 and Zbtb11; (d) Module M4, which includes Cdc40, Ddx41, Plrg1, Ppil2, Ppwd1, Prpf19, Prpf4, Sart1, Smu1, Snrnp40 and Wdr70; (e) Module M5, which includes Acaca, Ambra1, Amfr, Arih1, Cbll1, Cfap57, Cnot4, Cyld, Dcaf7, Det1, Dpf2, Eed, Efcab8, Egr2, Fasn, Fb xw7, Foxo3, Gsk3b, Hectd3, Hira, Icos, Ifnar1, Ikbke, Ints12, Junb, Kat6a, Kctd10, Kctd13, Kctd21, Kctd5, Klhl30, Klhl6, Lztr1, March6, Msl2, Nf1, Nfkb1, Nsd1, Patz1, Pias1, Prdm1, Pten, Rfwd2, Rnf139, Socs3, Spag16, Strap, Stub1, Syk, Tab1, Tank, Tbk1, Tnf, Trim45, Trip12, Ube2j2, Wdfy2, Wdr61, Wdr81, Wdr91, Zbtb25, Zfp106, Zfp91 and Zmiz2; and (f) Module M6, which includes Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fbxw11, Fus, Gm9840, Hif1a, Huwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, Ranbp2, Rbb p6, Rbck1, Rbx1, Rc3h1, Rela, Rlim, Rnf144a, Rnf31, Rnf7, Seh1l, Skp1a, Spop, Ssr3, Tbl1xr1, Tceb1, Tceb2, Tceb3, Tdpoz5 , Thoc3, Tlr4, Traf6, Trim28, Trim33, Ube2d3, Ube2f, Ube2h, Ube2i, Ubr4, Ubr5, Vhl, Wdr20, Wdr26, Wdr33, Zbtb17 and Zbtb7b.

103. A genetically modified isolated cell comprising alterations to at least two genes from one or more of the following gene sets: (a) Gene set 1, which includes Aamp, Actb, Alcam, Ambra1, Anxa2, Aprt, Atp5e, B2m, Btf3, Ccdc88a, Cdh1, Chd4, Cirh1a, Cox4i1, Cox7a2l, Crebbp, Ctsb, Dcaf13, Ddx41, Eef1a1, Eef1b2, Eef1g, Eef2, Eif1, Eif3e, Eif3f, Eif3i, Eif3k, Fau, Gapdh, H2-D1, H2-K1, H2-M2, Hsp90ab1, Hspa 5. Hspa8, Il1rn, Laptm5, Lhfpl2, March6, Ms4a7, Mtor, Myc, Naca, Ncl, Nf1, Nol10, Npm1, Ogt, Pabpc1, Paf1, Plrg1, Pparg, Psap, Rac k1, Raf1, Rheb, Rpl10, Rpl10a, Rpl11, Rpl12, Rpl13, Rpl13a, Rpl14, Rpl15, Rpl17, Rpl18, Rpl18a, Rpl19, Rpl21, Rpl22, Rpl22l1, Rp l23, Rpl23a, Rpl24, Rpl26, Rpl27a, Rpl28, Rpl29, Rpl3, Rpl30, Rpl31, Rpl32, Rpl34, Rpl35, Rpl35a, Rpl36, Rpl36a, Rpl37, Rpl37a, Rpl38, Rpl39, Rpl4, Rpl41, Rpl5, Rpl6, Rpl7, Rpl7a, Rpl8, Rpl9, Rplp0, Rplp1, Rplp2, Rps10, Rps11, Rps12, Rps13, Rps14, Rps15, Rp s15a, Rps16, Rps17, Rps18, Rps19, Rps2, Rps20, Rps21, Rps23, Rps24, Rps25, Rps26, Rps27, Rps27a, Rps28, Rps29, Rps3, Rps3a1, Rps 4x, Rps5, Rps6, Rps7, Rps8, Rps9, Rpsa, Rptor, Sgk1, Ssr4, Tab1, Taf5, Tpt1, Uhrf1, Uqcrh, Utp15, Wdr3, Wdr36, Wdr43, Wdr5 and Zbtb25; (b) Gene set 2, which includes AI314180, Abcc1, Acod1, Akr1a1, Alas1, Alox5ap, Ampd3, Arih1, Ass1, B430306N03Rik, Bach1, Blvrb, Bmi1, Brca1, Btbd1, Btg1, Cat, Ccr5, Cd36, Cd52, Cd53, Cd81, Chd4, Chpf2, Clec4n, Crebbp, Creg1, Cul3, Cx cl3, Cyb5a, Dap, Dars, Dck, Ddb1, Ddit3, Egr2, Eif3f, Eif3i, Ep300, Esd, Fbxl5, Fbxw11, Gbe1, Gclm, Gdap10, G m9840, Gss, Gstm1, H3f3b, Hmox1, Hvcn1, Il1f9, Inhba, Keap1, Lipa, Lmo4, Map3k7, Mcl1, Mcoln2, Met, Mgst2, Mm p12, Mmp19, Mmp8, Mylip, Nampt, Nedd8, Nf1, Npy, Nrp1, Nup43, Nupr1, Paf1, Pf4, Pgd, Phlda1, Pla2g7, Plet1, P pfibp2, Prdx1, Prdx6, Preb, Prkcb, Procr, Ptgr1, Ptpn1, Raf1, Rbx1, Rhob, Rnasel, Rnf128, Runx2, Sdc4, Sec13 , Seh1l, Skp1a, Slc43a2, Slc48a1, Slc7a11, Slpi, Smad2, Srxn1, Taldo1, Tarm1, Thbs1, Tlr2, Tlr4, Tma16, Tpm 4. Traf2, Traf5, Traf6, Trip12, Tubb2a, Txnrd1, Ube2d3, Ube2n, Ubr5, Uchl1, Upf1, Wdr43, Wdr61, Zbtb17 and Zyx; (c) Gene set 3, which includes Acp5, Ankfy1, Arpc1b, Atp6v0d2, Bptf, Brap, C5ar1, Ccdc88a, Cd14, Cd36, Cd63, Cebpb, Chd4, Clec4d, Clec5a, Cpd, Creg1, Ctsb, Ctsz, Cul3, Ddhd1, Dnmt3a, Egr2, Emb, F630028O10Rik, Fabp5, Fam46c, Fbxo42, Fcgr2b, Fn1, Foxo3, Fpr1, Ftl1, Gadd45a, Glrx, G pnmb, Gpr84, Huwe1, Icam1, Id1, Il1f9, Kctd10, Keap1, Klhl6, Lcn2, Lgals1, Lgals3, Lgmn , Lipa, Lpcat2, Ly6c2, March6, Metrnl, Mgll, Mt1, Mtor, Myof, Naaa, Naca, Nf1, Paf1, Phlda1, Pid1, Pik3r4, Pld3, Plet1, Plk2, Pou2f2, Pparg, Prdx5, Psap, Ptpn11, Rab3il1, Rela, Rfwd2, Rnase2a, S100a1, S100a11, S100a8, Saa3, Sdc3, Serpinb2, Slamf7, Snx18, Sod2, Sp ata13, Stap1, Strap, Tab1, Tceb2, Tgfbi, Thbs1, Trem1, Upf1, Upp1, Vat1, Wdfy3, Wfdc21, 2010005H15Rik and Zbtb25; (d) Gene set 4, which includes AC160336.1, Actb, Actg1, Ankfy1, Arhgdib, Bptf, Brap, Bri3, Ccr2, Ccr5, Cd274, Cdkn1a, Cfl1, Chd4, Clec4a2, Copa, Coro1a, Cotl1, Crip1, Cul1, Cul3, Dars, Ddhd1, Ddit3, Ear2, Eif3f, Eif3i, Ep300, Fbxw11, Flna, Gbp2, Gbp5, Grb2, Gtf3c1, H2-D1, H2-K1, Huwe1, If i27l2a, Il1rn, Keap1, Klk1b1, Lcp1, Lgals1, Lpl, Lrr1, Lsp1, Malat1, Marcksl1, Med8, Mgll, Mndal, Mtor, Naca, Nedd8, Nf1, Paf1, Pfn1, Pi k3r4, Pten, Ptma, Ptpn11, Rack1, Rela, Rnf20, Sdc4, Skp1a, Taf3, Taf5, Tlr4, Tmsb4x, Ubb, Ube2i, Upf1, Vhl, Wdfy3, Wdr43, Wdr82 and Wfdc17; (e) Gene set 5, which includes AA467197, AW112010, Abcg1, Acod1, Bcl2a1b, Bcl2a1d, Cav1, Ccl17, Ccl3, Ccl4, Cd14, Cd200r1, Cd300lf, Cdkn1a, Cebpb, Cflar, Chd4, Clec4e, Clic4, Copa, Cpd, Cpeb4, Cul1, Cul3, Cx cl1, Cxcl2, Cxcl3, Ehd1, Ep300, Fam102b, Fam20c, Fbxw11, Gda, Gpr84, Hist1h1c, Hivep3, Ikbke, I kbkg, Il12b, Il1a, Il1b, Il6, Ing3, Inhba, Kctd21, Klf4, Laptm5, Mafb, Malat1, Malt1, Marcks, Ma rcksl1, Marco, Met, Mtpn, Nabp1, Nedd8, Nfkb1, Nfkbiz, Nlrp3, Nrp2, Nup62, Ogt, Paf1, Plek, Plrg 1. Ppfia3, Prpf19, Ptgs2, Ptx3, Rassf4, Rbx1, Rela, Rfwd2, Rnf31, Serpinb2, Sh3bp5, Skp1a, Slc7 a11, Slc7a2, Slco3a1, Slfn2, Smad2, Smu1, Socs6, Sod2, Spop, Stub1, Tank, Tbk1, Tceb3, Tlr4, Tnf , Tnfaip3, Tnfsf15, Tradd, Traf6, Trip12, Txnip, Ube2d3, Ube2i, Ube2n, Wdr82, Zbtb17 and Zc3h12c; (f) Gene set 6, which includes AA467197, Ahr, Akt1, Ankfy1, Axl, Bhlhe40, Bhlhe41, Btg1, Ccl17, Ccl22, Ccr2, Cd40, Cd52, Cd74, Cebpb, Chd4, Clec4e, Clec4n, Clic4, Cst3, Cstf1, Ctsb, Ctsd, Cxcl16. Dcstamp, Egr2, Etv3, Fabp4, Fabp5, Fam20c, Fbxw7, Fbxw9, Foxo3, Fpr1, Fth1, Ftl1, Gbp2, G bp5, Gm2a, Gnb1, Gnb2, Grb2, Grk3, Gsk3b, H2-Aa, H2-Ab1, Hmox1, Igf1, Il4i1, Irf4, Itgax, J ak2, Jund, Kcmf1, Klhl6, Kmt2d, Lgals1, Lyz2, March6, Mgl2, Mmp12, Mtor, Myc, Ndufa4, Nec tin2, Nf1, Nfkb1, Pfkp, Pid1, Pik3r4, Plet1, Pmp22, Pten, Ptpn1, Ptpn11, Rheb, Rilpl2, Rp tor, S100a8, Sart1, Scimp, Sdcbp, Sema4a, Sgk1, Slamf9, Smad2, Srgn, Stat5a, Tab1, Taf5l , Tank, Tceb1, Tceb2, Tlr2, Tlr4, Traf2, Traf3, Ube2n, Vcan, Wdfy3, Wdr26, Wdr61 and Zfp36l1; (g) Gene set 7, which includes Abca1, Actb, Ambra1, Atf4, Atp5g1, Atp5j, Atp5j2, Bcl2a1b, Calm1, Cfl1, Chd4, Copa, Copb2, Cotl1, Cox8a, Cul3, Cybb, Dbi, Ddit3, Eef1a1, Eif3f, Eif3i, Fbxo28, Fcer1g, Gpx1, Grb2, H2-M2, H2afz, H3f3a, Il1rn, Inhb a, Keap1, Kmt2d, Lhfpl2, Ly6e, March6, Med8, Mtor, Nedd8, Nf1, Nme1, Ogt, Paf1, Plrg1, Pnp, Pparg, Rack1, S100a10 , S100a4, S100a6, Sdc4, Sec13, Serf2, Sgk1, Smad2, Smu1, Sqstm1, Tab1, Taf3, Trp53, Uhrf1, Wdr43, Wdr61 and Zbtb25; (h) Gene set 8, which includes Aamp, Acsl1, Ambra1, Arf4, Arih2, Atf4, Bop1, C1qb, Calr, Canx, Ccng1, Cdkn1a, Chd4, Cirh1a, Clec2d, Copa, Copb2, Cope, Cpd, Ctss, Cul3, Dad1, Dap, Dcaf13, Ddit3, Ddx41, Dstn, Eif 3f, Eif3i, Erp29, Fbxw7, Fth1, Ftl1, Gm9840, Grb2, Gtf3c1, Herpud1, Hif1a, Hnrnpa3, Hsp90b1, Hs pa5, Ift20, Keap1, Kmt2d, Krtcap2, Lgals3, Lrr1, Lyz2, Manf, Map3k7, Mthfd2, Mtor, Myc, Naca, Ne dd8, Nf1, Nol10, Ostc, P4hb, Pdia3, Pdia4, Pdia6, Phgdh, Plrg1, Preb, Prpf19, Pten, Ptpn1, Rack1 , Rbx1, Rela, Rpl22l1, Rpn1, Rps19, Rrp9, Sdf2l1, Sec11c, Sec13, Sec22b, Sec31a, Sec61b, Sec61g , Selenos, Serf2, Serp1, Sf3b5, Spcs2, Ssr3, Surf4, Syvn1, Tceal9, Tceb1, Tceb2, Timm13, Tpt1, T ram1, Trp53, Ube2f, Ufm1, Uqcrq, Utp15, Vcp, Vhl, Vprbp, Wdr36, Wdr43, Wdr5, Wdr74, Wdr75 and Xbp1; (i) Gene set 9, which includes Acod1, Adam8, Atp5g3, Brap, C3ar1, Ccl2, Ccl3, Ccl4, Ccl7, Ccnd1, Cd300ld, Cd63, Ch25h, Chd4, Chil3, Crip1, Ctsb, Ctsl, Cul1, Cul3, Cxcl1, Cyp51, Det1, Ear2, Egr2, F10, Fbxo42, F bxw11, Ffar2, Fpr2, Fyb, Gas7, Gm9840, Gnb2, Gpnmb, Grb2, Gsk3b, Hmgcs1, Huwe1, Ifitm3, Il1f9, Itgam, Jun, Kctd12, Kctd5, Keap1, Klhdc4, Kmt2c, Kmt2d, Lgals1, Lgals3, Lmna, Lmo4, Lrpap1, Ly6 c2, Lztr1, Maf, March6, Mcemp1, Mmp12, Mmp13, Mmp8, Msr1, Mtor, Naaa, Naca, Nf1, Nfkbiz, Npc2, N py, Paf1, Pdpn, Pf4, Plet1, Pparg, Prkcd, Pten, Ptgs2, Ptpn1, Ptpn11, Ptprc, Ptx3, Rbbp5, Rela, R fwd2, Rheb, Rptor, S100a6, Saa3, Scap, Scd2, Serpinb2, Serpinb6a, Sgk1, Slc7a11, Smad2, Srgn, Syk, Syngr1, Timp2, Trem2, Ube2h, Ube2i, Ucp2, Vasp, Vhl, Wdr26, Wfdc21, Ybx1, Zbtb7a and Zfp36l2; (j) Gene set 10, which includes Acaca, Ak4, Aldoa, Aldoc, Anapc13, Anxa2, Arih2, Arnt, Basp1, Bnip3l, Bsg, C3ar1, Ccl9, Cd52, Chil3, Copa, Cul2, Cul3, Cul5, Egr2, Eif3i, Eif4ebp1, Emilin2, Eno1, Ep300, Fam162a, Gapdh, Gbe1, Gpi1, Gsn, Herpud1, Hif1a, Higd1a, Hilpda, Hk1, Hk2, Hmox1, Huwe1, Ier3, Kctd10, Klk1b1, Ldha, Lgals3, Lipa, Lmo4, Lpcat2, L yz2, March6, Mif, Mt1, Mt2, Mtor, Myc, Ndufv3, Nf1, Pdk1, Pfkl, Pgam1, Pgk1, Pgm2, P km, Prdx1, Prelid1, Ptpn1, Ptpn11, Rbpj, Rfwd2, Rilpl2, Rnase2a, Sacs, Scd2, Sdc3, Sdc4, Sec13, Slamf9, Slc16a3, Slc2a1, Slc7a2, Smu1, Socs3, Strap, Tarm1, Tceb1, T ceb2, Tgm2, Tlr4, Tpi1, Trf, Ube2f, Vhl, Vim, Wdr43, Wdr82, Wfdc17 and 2010005H15Rik; (k) Gene set 11, which includes AA467197, Apobec1, Apoe, C1qa, C1qb, C1qc, C3, Car4, Ccl22, Ccl3, Ccl4, Ccl6, Ccl9, Cd83, Cdc40, Cebpb, Ch25h, Chd4, Copa, Crebbp, Cul1, Ddhd1, Ddx41, Egr2, Eif3f, Eif3i, Ep300, Fam49a, Fbxw11, Fn1, Fnbp1l, Gadd45b, Hdac4, Icam1, Icosl, Id2, Ikbkg, Il1a, Il4i1, Inhba, Itgax, Itgb2, Kctd10, Klk1b11, Lpl, Maf, Marks, Marksl1, M ed8, Met, Mmp12, Ms4a6c, Ms4a7, Mt2, Mycbp2, Naca, Nedd8, Nfkbia, Phlda1, Plaur, Plrg1, Pparg, Ppfibp2, Prpf19, Ptpn1, Rassf4, Rfwd2, Ring1, Rnase2a, Rpl12, Scimp, Sec13 ,Skp1a,Slc43a2,Smu1,Sqstm1,Syk,Syvn1,Taf5l,Tceb2,Tmem176a,Tmem176b,Tnfaip 2. Traf3, Ufm1, Upp1, Wdr5, Wdr70, Wdr82, Wfdc17, Wfdc21, 0610012G03Rik, Zbtb7a and Zyx; (l) Gene set 12, which includes Ambra1, Aplop2, Atp5g1, Atpif1, B2m, Ccdc88a, Chd4, Copa, Cyba, Ddit3, Ear2, Egr2, Eif3f, Eif3i, Eif5, Fcgrt, Grn, H2-M2, H2-Q6, Hint1, Id1, Ifi204, Itgal, Kctd12, Laptm5, Lgals3, Ly6e, Mgst1, Mpeg1, Mtdh, Nf1 Nfe2l2, Nupr1, Paf1, Pparg, Prpf19, Psmb5, Psmb6, Pycard, Rack1, Rnase4, Rpl22l1, Rpl37a, Rplp0, Sart1, Sdc3, S ec61b, Smad2, Smdt1, Smu1, Spp1, Syvn1, Tab1, Taf5, Taf5l, Tagln2, Tmsb10, Traf2, Traf3, Trf, Trp53, Upf1 and Wdr5; (m) Gene set 13, which includes Ankfy1, Anxa1, Anxa5, Aph1c, Brap, C3ar1, Ccnd2, Ccr1, Cd300lf, Cd38, Cd68, Cd9, Cdc27, Cdc40, Cebpb, Chd4, Chst11, Clec4e, Creb5, Cul1, Cul3, Cxcl3, Cyba, Dstn, Eif3f, Eif3i, Emp1, Epha4, Fam102b, Fam46a, Fbxw11, Fn1, Foxo3, Ftl1, Furin, Gas7, Gdf15, Grb2, H2-K1, Huwe1, Icam1, Il7r, Inhba, Keap1, Klhdc4, Klk1b11, Lgal s3, Lpl, Ly6c2, Lyz2, March6, Mbnl1, Mmp14, Mmp8, Ms4a7, Naca, Neat1, Nf1, Nrp2, Pli n2, Plk2, Plrg1, Polr2l, Prdx1, Pten, Ptpn1, Rack1, Rasgef1b, Rasgrp1, Rela, Rnf20, Rnh1, Rpl22l1, Rrp9, Saa3, Scd2, Sdc4, Sec13, Selenoh, Serp1, Skp1a, Slamf7, Slc7a2 , Smu1, Spp1, Tab1, Taf5, Ube2d3, Ubr4, Upf1, Vim, Wdr43, Wdr5, Wdr70, Wdr82 and Zbtb25; (n) Gene set 14, which includes AC160336.1, Adgre1, Adgre4, Adgrl2, Anxa1, B2m, C1qb, C3, Car4, Ccdc88a, Ccl6, Cd52, Cdc40, Chd4, Chil3, Crip1, Ctsk, Ddx41, Dpf2, Egr2, Eif3i, Ep300, F7, Fcer1g, Fn1, Foxo3, Gpx3, H2-D1, H2-K1, H2-Q6, H2-Q7, H3f3b, Hira, Hsp90aa1, Hvcn1, Id2, Ifi203, Il18, Il1f9, Kdm5c, Klhl6, Lgals1, Lgals3, Ly6e, Malt1, March6, Marks. Mcub, Med8, Mpc1, Ms4a6d, Msrb1, Mt1, Mt2, Nedd8, Nfe2l2, Nov, Npc2, Paf1, Pdzk1ip1, Phgdh, Pias1, Pla2g7, Plrg1, Ppic, Ppil2, Ppwd1, Prkcd, Prpf19, Ptges, Rab32, Rbx1, and (o) Gene set 15, which includes AC160336.1, Adgre1, Ahnak, Alcam, Aprt, Bcl2l11, Blvrb, Brap, Bub3, C1qb, C1qc, C3ar1, Cd300c2, Cd33, Cd68, Cdc40, Cebpb, Chchd2, Clec12a, Clec4n, Copa, Csf1r, Ctsz, Cul3, Cul5, Cyba, Ddx41, Dstn, Egr2, Ep300, F7, Fbxw7, Fcer1g, Fcgr2b, Gmfg, Gngt2, Gpr84, Hsp90aa1, Huwe1, Igf1, Kat6a, Kctd12b, Kdm5c, Keap1, Kmt2d, Ls t1, Mmp14, Mpeg1, Myc, Naca, P2ry14, Paf1, Pirb, Plrg1, Pou2f2, Pparg, Ppil2, Ppwd1 , Prkcd, Prpf19, Prpf4, Ptpn1, Ptpn18, Rack1, Rbbp5, Rnf20, Rnf40, Rnf7, Rps27l, Sat 1. Serpinb2, Smu1, Socs3, Spp1, Taf5, Tank, Tceb1, Tceb2, Tgm2, Tnfsf15, Traf2, Tre m2, Tyrobp, Ufm1, Vcan, Wdr1, Wdr33, Wdr43, Wdr5, Wdr61, Wdr70, Wdr82, Wfdc21 and Ybx1.

104. The method according to any one of claims 93 to 95, the kit according to any one of claims 97 to 101, or the genetically modified cells according to claim 102 or 103, wherein at least one of the modifications is a loss-of-function modification.

105. The method according to any one of claims 93 to 95, the kit according to any one of claims 97 to 101, or the genetically modified cells according to claim 102 or 103, wherein at least one of the modifications is a gain-of-function modification.

106. The method according to any one of claims 93 to 95, the kit according to any one of claims 97 to 101, or the genetically modified cells according to claim 102 or 103, wherein the genetically modified isolated cells comprise loss-of-function alterations of one, two, or all three of Ldb2, Rnf165, and Traf2.

107. The method of claim 106 or the genetically modified cell, wherein the loss-of-function alteration is a knockout (KO) mutation.

108. The method of any one of claims 93 to 95, the kit of any one of claims 97 to 101, or the genetically modified cells of claim 102 or 103, wherein the genetically modified isolated cells contain gain-of-function alterations to CCR7.

109. The method of claim 108 or the genetically modified cell, wherein the gain-of-function alteration is overexpression.

110. A method for identifying a modulator of interaction between an F-box and a WD repeating domain 11 (Fbxw11) and a nuclear factor κB subunit 1 (Nfkb1) or a nuclear factor κB subunit 2 (Nfkb2), the method comprising: (a) Providing candidate regulators; (b) Contact Fbxw11 with Nfkb1 or Nfkb2 in the presence or absence of the candidate regulator, under conditions that allow the binding of Fbxw11 with Nfkb1 or Nfkb2; as well as (c) Measure the binding of Fbxw11 with Nfkb1 or Nfkb2, wherein an increase or decrease in the binding in the presence of the candidate regulator relative to the binding in the absence of the candidate regulator identifies the candidate regulator as a regulator of the interaction between Fbxw11 and Nfkb1 or Nfkb2.

111. A method for identifying regulators of downstream activity of Fbxw11, the method comprising: (a) Providing candidate regulators; (b) Contacting Fbxw11 with Nfkb1 or Nfkb2 in the presence or absence of the candidate modifier, under conditions that allow for the binding of Fbxw11 with Nfkb1 or Nfkb2; and (c) Measuring the downstream activity of Fbxw11, wherein the change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of Fbxw11.

112. A method for identifying regulators of downstream activity of Nfkb1 or Nfkb2, the method comprising: (a) Providing candidate regulators; (b) Contacting Nfkb1 or Nfkb2 with Fbxw11 in the presence or absence of the candidate regulator, under conditions that allow Nfkb1 or Nfkb2 to bind with Fbxw11; as well as (c) Measure the downstream activity of Nfkb1 or Nfkb2, wherein the change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of Nfkb1 or Nfkb2.

113. The method of claim 110, wherein the increase or decrease in binding is at least 50%, as measured by surface plasmon resonance, biolayer interference, or enzyme-linked immunosorbent assay (ELISA).

114. The method according to any one of claims 110 to 113, wherein the modulator is an inhibitor of the downstream activity of Fbxw11, Nfkb1, or Nfkb2.

115. The method of claim 111 or 112, wherein the change in downstream activity is an increase in the amount, intensity, or duration of the downstream activity.

116. The method of claim 111 or 112, wherein the change in downstream activity is a reduction in the amount, intensity, or duration of the downstream activity.

117. The method according to any one of claims 110 to 116, wherein the modulator is a protein hydrolysis-targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or an inhibitory nucleic acid.

118. The method of claim 117, wherein the inhibitory nucleic acid is ASO or siRNA.

119. The method according to claim 117, wherein the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, a bisomatic antibody, a linear antibody, scFv, scFab, a VH domain, or a VHH domain.

120. The method of claim 117 or 119, wherein the antibody or its antigen-binding fragment binds to Fbxw11.

121. The method according to claim 117 or 119, wherein the antibody or its antigen-binding fragment binds to Nfkb1 or Nfkb2.

122. The method according to any one of claims 111 to 121, wherein the downstream activity is immune response activation.

123. A method for preventing or treating an individual's cancer, inflammatory disease, or autoimmune disease, the method comprising administering to the individual an effective amount of a modulator identified by the method according to any one of claims 110 to 122, thereby treating the individual.

124. A method for treating cancer in an individual, the method comprising administering to the individual an effective amount of a modulator of the interaction between Fbxw11 and one or both of Nfkb1 and Nfkb2, wherein activation of an immune response is increased in the presence of the modulator.

125. A method for treating an individual with an inflammatory disease or an autoimmune disease, the method comprising administering to the individual an effective amount of a modulator of the interaction between Fbxw11 and one or both of Nfkb1 and Nfkb2, wherein activation of the immune response is reduced in the presence of the modulator.

126. A method for identifying regulators of the interaction between the ring finger and WD repeat domain 2 (Rfwd2) and a query protein selected from Forkhead Box L2 (Foxl2), JunD, WD repeat domain 82 (Wdr82); E1A-binding protein p300 (Ep300); late-promoting complex subunit 13 (Anapc13); Cullin 2 (Cul2); Cullin 5 (Cul5); E3 ubiquitin ligase 1 (Huwe1) containing HECT, UBA, and WWE domains; CREB-binding protein (Crebbp); S-phase kinase-associated protein 1 (Skp1a); developmentally downregulated gene 8 expressed in neural progenitor cells (Nedd8); Cullin 1 (Cul1); and WD repeat domain 5 (Wdr5), the method comprising: (a) Providing candidate regulators; (b) Contacting Rfwd2 with the query protein in the presence or absence of the candidate regulator under conditions that allow Rfwd2 to bind to the query protein; as well as (c) Measuring the binding of Rfwd2 to the query protein, wherein an increase or decrease in binding in the presence of the candidate regulator relative to binding in the absence of the candidate regulator identifies the candidate regulator as a regulator of the interaction between Rfwd2 and the query protein.

127. A method for identifying regulators of downstream activity of Rfwd2, the method comprising: (a) Providing candidate regulators; (b) Contacting Rfwd2 with a query protein, selected from Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5, in the presence or absence of the candidate regulator, under conditions allowing Rfwd2 to bind to the query protein; and (c) Measuring the downstream activity of Rfwd2, wherein the change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of Rfwd2.

128. A method for identifying regulators of downstream activity of a query protein selected from Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5, the method comprising: (a) Providing candidate regulators; (b) Contact the query protein with Rfwd2 in the presence or absence of the candidate regulator under conditions that allow the query protein to bind to Rfwd2; as well as (c) Measuring the downstream activity of the query protein, wherein the change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of the query protein.

129. The method of claim 126, wherein the increase or decrease in binding is at least 50%, as measured by surface plasmon resonance, biolayer interference, or enzyme-linked immunosorbent assay (ELISA).

130. The method according to any one of claims 126 to 129, wherein the regulator is Rfwd2 or an inhibitor of the downstream activity of the query protein.

131. The method of claim 127 or 128, wherein the change in downstream activity is an increase in the amount, intensity, or duration of the downstream activity.

132. The method of claim 127 or 128, wherein the change in downstream activity is a reduction in the amount, intensity, or duration of the downstream activity.

133. The method according to any one of claims 126 to 132, wherein the modulator is a protein hydrolysis-targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or an inhibitory nucleic acid.

134. The method of claim 133, wherein the inhibitory nucleic acid is ASO or siRNA.

135. The method according to claim 133, wherein the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, a bisomatic antibody, a linear antibody, scFv, scFab, a VH domain, or a VHH domain.

136. The method of claim 133 or 135, wherein the antibody or its antigen-binding fragment binds to Rfwd2.

137. The method of claim 133 or 135, wherein the antibody or its antigen-binding fragment binds to the query protein.

138. The method according to any one of claims 127 to 137, wherein the downstream activity is dendritic cell or macrophage migration.

139. A method for preventing or treating an individual's cancer, inflammatory disease, or autoimmune disease, the method comprising administering to the individual an effective amount of a modulator identified by the method according to any one of claims 126 to 138, thereby treating the individual.

140. A method for treating an individual with an inflammatory disease or an autoimmune disease, the method comprising administering to the individual an effective amount of a modulator of the interaction between Rfwd2 and one or more of Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5, wherein dendritic cell or macrophage migration is reduced in the presence of the modulator.

141. A method for treating cancer in an individual, the method comprising administering to the individual an effective amount of a modulator of the interaction between Rfwd2 and one or more of Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5, wherein dendritic cell or macrophage migration is increased in the presence of the modulator.

142. A kit comprising a modulator of the interaction between Rfwd2 and one or more of Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1 and Wdr5, said kit being used to treat an individual suffering from cancer, an inflammatory disease or an autoimmune disease by the method of any one of claims 139 to 141.

143. The kit of claim 142, wherein the kit includes a packaging insert containing instructions for administering the modulator to an individual suffering from cancer, an inflammatory disease, or an autoimmune disease.

144. A method for identifying regulators of interactions between a protein complex and a CCAAT enhancer-binding protein (Cebp) family transcription factor, said protein complex comprising a non-receptor tyrosine protein phosphatase 11 (Ptpn11) and a ring finger and WD repeat domain 2 (Rfwd2), said method comprising: (a) Providing candidate regulators; (b) Contacting the protein complex with the Cebp family transcription factor in the presence or absence of the candidate regulator, under conditions that allow Rfwd2 to bind to the query protein; and (c) Measuring the binding of the protein complex to the Cebp family transcription factor, wherein an increase or decrease in binding in the presence of the candidate regulator relative to binding in the absence of the candidate regulator identifies the candidate regulator as a regulator of the interaction between the protein complex and the Cebp family transcription factor.

145. A method for identifying regulators of downstream activity of a protein complex comprising Ptpn11 and Rfwd2, the method comprising: (a) Providing candidate regulators; (b) Contact the protein complex with Cebp family transcription factors in the presence or absence of the candidate regulator, under conditions that allow the protein complex to bind to the Cebp family transcription factors; as well as (c) Measuring the downstream activity of the protein complex, wherein the change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of the protein complex.

146. A method for identifying regulators of downstream activity of Cebp family transcription factors, the method comprising: (a) Providing candidate regulators; (b) Contact the Cebp family transcription factor with a protein complex containing Ptpn11 and Rfwd2 in the presence or absence of the candidate regulator, under conditions that allow the Cebp family transcription factor to bind to the protein complex. as well as (c) Measuring the downstream activity of the query protein, wherein the change in the downstream activity in the presence of the candidate regulator relative to the downstream activity in the absence of the candidate regulator identifies the candidate regulator as a regulator of the downstream activity of the query protein.

147. The method of claim 144, wherein the increase or decrease in binding is at least 50%, as measured by surface plasmon resonance, biolayer interference, or enzyme-linked immunosorbent assay (ELISA).

148. The method according to any one of claims 144 to 147, wherein the regulator is an inhibitor of the downstream activity of the protein complex or the Cebp family transcription factor.

149. The method of claim 145 or 146, wherein the change in downstream activity is an increase in the amount, intensity, or duration of the downstream activity.

150. The method of claim 145 or 146, wherein the change in downstream activity is a reduction in the amount, intensity, or duration of the downstream activity.

151. The method according to any one of claims 144 to 150, wherein the modulator is a protein hydrolysis-targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or an inhibitory nucleic acid.

152. The method of claim 151, wherein the inhibitory nucleic acid is ASO or siRNA.

153. The method according to claim 151, wherein the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, a bisomatic antibody, a linear antibody, scFv, scFab, a VH domain, or a VHH domain.

154. The method of claim 151 or 153, wherein the antibody or its antigen-binding fragment binds to the protein complex.

155. The method of claim 151 or 153, wherein the antibody or its antigen-binding fragment binds to the Cebp family transcription factor.

156. A method for preventing or treating an individual’s disease or condition associated with antigen-presenting cells (APCs) and / or inflammation, the method comprising administering to the individual an effective amount of a regulator of a gene from Table 1 or Table 2, thereby treating the individual.

157. The method of claim 156, wherein the regulator regulates the expression of the gene.

158. The method of claim 156, wherein the regulator regulates the expression or activity of the protein encoded by the gene.

159. The method according to any one of claims 156 to 158, wherein the regulator causes a change in the downstream activity of the protein encoded by the gene of Table 1 or Table 2 in the presence of the regulator relative to the downstream activity in the absence of the regulator.

160. The method of claim 159, wherein the regulator is an inhibitor of the downstream activity of the gene in Table 1 or Table 2.

161. The method of claim 159 or 160, wherein the change in downstream activity is a reduction in the amount, intensity, or duration of the downstream activity.

162. The method of claim 159, wherein the regulator is an activator of the downstream activity of the gene in Table 1 or Table 2.

163. The method of claim 159 or 162, wherein the change in downstream activity is an increase in the amount, intensity, or duration of the downstream activity.

164. The method according to any one of claims 156 to 163, wherein the modulator is a protein hydrolysis-targeting chimera (PROTAC), a small molecule, an antibody or its antigen-binding fragment, a peptide, a mimic, or an inhibitory nucleic acid.

165. The method of claim 164, wherein the inhibitory nucleic acid is ASO or siRNA.

166. The method according to claim 164, wherein the antigen-binding fragment is a bi-Fab, Fv, Fab, Fab'-SH, F(ab')2, a bisomatic antibody, a linear antibody, scFv, scFab, a VH domain, or a VHH domain.

167. The method of claim 164 or 166, wherein the antibody or its antigen-binding fragment binds to a protein encoded by the gene in Table 1 or Table 2.

168. The method according to any one of claims 156 to 167, wherein the disease or condition associated with APC and / or inflammation is a neurodegenerative disease, arthritis, allergic reaction, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or blastic plasmacytoid dendritic cell tumor.

169. The method of claim 168, wherein the neurodegenerative disease is MS, AD, ALS, or PD.

170. The method according to any one of claims 156 to 169, wherein the APC is a DC, a macrophage, or a glial cell.

171. The method according to claim 170, wherein the glial cells are microglia, astrocytes, or oligodendrocytes.

172. The method of claim 170, wherein the APC is a DC.

173. A kit comprising regulators of genes listed in Table 1 or Table 2, said kit being used to treat an individual suffering from a disease or condition associated with APC and / or inflammation using the method described in any one of claims 156 to 172.

174. The kit of claim 173, wherein the kit includes a packaging insert containing instructions for administering the modulator to an individual suffering from a disease or condition associated with APC and / or inflammation.

175. A method for monitoring the response of an individual suffering from a disease or condition associated with APC and / or inflammation to treatment with a regulator of the genes listed in Table 1 or Table 2, the method comprising: (a) Determine the expression levels of the genes in Table 1 or Table 2 in biological samples obtained from the individual at a time point following the administration of the regulator; as well as (b) The expression levels of the genes in Table 1 or Table 2 in the biological sample are compared with reference levels to monitor the individual's response to treatment with the modulator.

176. The method of claim 175, wherein the reference level is selected from the group consisting of: (i) the expression level of the gene in a biological sample obtained from the individual prior to the administration of the regulator; (ii) the expression level of the gene in a reference population; (iii) a pre-specified expression level for the gene; or (iv) the expression level of the gene in a biological sample obtained from the individual at a previous time point, wherein the previous time point is after the administration of the regulator.

177. The method of claim 175 or 176, wherein the expression level of the gene in Table 1 or Table 2 in the biological sample obtained from the individual is reduced relative to the reference level, and the method further comprises administering one or more additional doses of the modulator to the individual, wherein the modulator is an agent that increases the expression and / or activity of the gene in Table 1 or Table 2.

178. The method of claim 175 or 176, wherein the expression level of the gene in Table 1 or Table 2 in the biological sample obtained from the individual is increased relative to the reference level, and the method further comprises administering one or more additional doses of the modulator to the individual, wherein the modulator is an agent that reduces the expression and / or activity of the gene in Table 1 or Table 2.

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