Functions and interactions of the E3 ligase family

Abstract

Provided herein are methods for treating cancer, inflammatory diseases, and autoimmune diseases and modulating associated phenotypes and expression levels by targeting interactions between E3 ligases, E3-like proteins, and their interacting partners. Methods for identifying modulators of such interactions are also provided. Also provided herein are cellular therapies comprising alterations in at least two members of a cofunctional gene module.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 440,365, filed January 20, 2023, and Japanese Patent Application Laid-Open No. 2023-186191, filed October 31, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] Statement Regarding Federally Funded Research This invention was made with government support provided under Grant No. 5RM1HGP706193-09 awarded by the Center of Excellence in Genomic Sciences (CEGS) of the National Human Genome Research Institute (NHGRI), and Grant No. 5F32AI138458 (F32) awarded by a Ruth L. Kirschstein National Research Service Award (NRSA) for an Individual Postdoctoral Fellowship from the National Institutes of Health (NIH). The U.S. Government has certain rights in this invention.

[0003] Provided herein are methods for treating cancer, inflammatory diseases, and autoimmune diseases and modulating associated phenotypes and expression levels by targeting interactions between E3 ligases, E3-like proteins, and their interacting partners. Methods for identifying modulators of such interactions are also provided. Also provided herein are cellular therapies comprising alterations in at least two members of a cofunctional gene module. [Background technology]

[0004] The human genome encodes over 600 E3 ubiquitin ligases, which are responsible for catalyzing the ligation of ubiquitin to substrates in nearly every biochemical pathway. Genome-wide association studies (GWAS) have implicated variants in E3 ligase genes in many diseases, including inflammatory and autoimmune diseases. Previous studies have implicated specific E3 ligases in the inflammatory response of dendritic cells to lipopolysaccharides, but the roles of E3 ligases, E3-like proteins, interacting partners, and their substrates in dendritic cells or other primary immune cells remain largely unknown. Therefore, there is a need in the art to elucidate novel roles and relationships between 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

[0005] In one aspect, the invention provides a method for treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method comprising administering to the individual an effective amount of a modulator of the interaction between (a) one, two, or all three of LIM domain-binding protein 2 (Ldb2), Ring finger protein 165 (Rnf165), and TNF receptor-associated factor 2 (Traf2), and (b) chemokine receptor type 7 (CCR7).

[0006] In some embodiments, the individual has cancer and the modulator is an agent that decreases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0007] In other aspects, 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.

[0008] In another aspect, the present invention provides a method for increasing 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 decreases 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).

[0009] In some embodiments, the APC is in an individual. In some embodiments, the individual has cancer.

[0010] In some embodiments, expression of CCR7 in the APC is increased by at least 10% compared to expression in the absence of the agent.

[0011] In another aspect, the present invention provides a method for increasing APC migration to tumors and / or lymph nodes in an individual, the method comprising administering to the individual an effective amount of an agent that decreases 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).

[0012] In some embodiments, the individual has cancer.

[0013] In some embodiments, migration of APCs to tumors and / or lymph nodes in an individual is increased by at least 10% compared to migration in the absence of the agent.

[0014] In some embodiments, the APC is a dendritic cell (DC), a macrophage, or a glial cell. In some embodiments, the glial cell is a microglial cell, an astrocyte, or an oligodendrocyte. In some embodiments, the APC is a DC.

[0015] In another aspect, the invention provides 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 decreases 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).

[0016] In some embodiments, T cell homing to the tumor in the individual is increased by at least 10% compared to T cell homing in the absence of the agent.

[0017] In some embodiments, the inflammatory or autoimmune disease is a neurodegenerative disease, arthritis, allergy, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some embodiments, the neurodegenerative disease is multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD). In some embodiments, the inflammatory or autoimmune disease is Crohn's disease.

[0018] In some aspects, the agent is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid.

[0019] In some embodiments, the inhibitory nucleic acid is an ASO or an siRNA.

[0020] In some embodiments, the antigen-binding fragment is a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain. In some embodiments, the antibody or antigen-binding fragment thereof binds to Ldb2, Rnf165, or Traf2. In some embodiments, the antibody or antigen-binding fragment thereof binds to CCR7. In some embodiments, the agent is a bispecific antibody comprising an antigen-binding domain that targets the tumor microenvironment.

[0021] In some embodiments, the methods further comprise administering to the individual or contacting the APCs with one or more additional agents.

[0022] In some embodiments, the method comprises the step of detecting a gene encoding an antibody against a gene encoding an antibody against one or more of: 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, Mlst8, Mtor, Nosip, Paf1, Pik3r4, Pparg, Ppp2r2a, Ppp2 The method further comprises administering to the individual or contacting the APC with one or more agents that modulate expression of one or more of r2d, Preb, Rbbp4, Rbbp5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13, Sec31a, Smad2, Syvn1, Taf51, Traf2, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1, and Zbtb11.

[0023] In another aspect, the invention provides kits comprising a modulator of the interaction between (a) one, two, or all three of Ldb2, Rnf165, and Traf2 and (b) CCR7 for treating an individual with cancer, an inflammatory disease, or an autoimmune disease by any one of the methods provided herein. In some aspects, the kit comprises a package insert containing instructions for administering the modulator to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0024] In another aspect, the invention provides 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, the method comprising: (i) determining the expression level of one or more of Ldb2, Rnf165, and Traf2 in a biological sample obtained from the individual at a time point after administration of the modulator; and (ii) comparing the expression level of one or more genes in the biological sample to a reference level, thereby monitoring the response in the individual to treatment with the modulator.

[0025] In some embodiments, 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 the individual prior to administration of the modulator; (ii) the expression level of one or more genes in a reference population; (iii) a pre-assigned expression level for one or more genes; or (iv) the expression level of one or more genes in a biological sample obtained from the individual at an earlier time point after administration of the modulator.

[0026] In some aspects, the individual has cancer and the expression level of one or more genes is increased in a biological sample obtained from the individual compared to a reference level, and the method further comprises administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that decreases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0027] In some aspects, the individual has an inflammatory or autoimmune disease, and the expression level of one or more genes is decreased in a biological sample obtained from the individual compared to a reference level, and the method further comprises administering one or more additional doses of a modulator to the individual; the modulator is an agent that increases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0028] In another aspect, the present invention provides a method for treating cancer, an inflammatory disease, an autoimmune disease, or an infectious disease in an individual, the method comprising administering to the individual an effective amount of (a) an agent that decreases the expression and / or activity of CCAAT / enhancer-binding protein beta (Cebpb); (b) an agent that decreases 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-inducer-obliterator 1 (Dido1).

[0029] In some aspects, autoimmune diseases are associated with a decreased proportion of migratory dendritic cells (mDCs).

[0030] In some embodiments, the individual has a loss-of-function mutation in Dido1.

[0031] In another aspect, the present invention provides a method for treating an inflammatory disease, autoimmune disease, or infectious disease 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 beta (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-inducer-obliterator 1 (Dido1).

[0032] 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 decreases the expression and / or activity of CCAAT / enhancer-binding protein beta (Cebpb); (b) an agent that decreases 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-inducer-obliterator 1 (Dido1).

[0033] In some embodiments, the rate is in an individual's tumor or tissue.

[0034] In some embodiments, the proportion of mDCs in the individual is increased by at least 10% compared to the proportion in the absence of the agent.

[0035] In another aspect, the present invention provides a method for increasing anti-tumor immunity in an individual, the method comprising administering to the individual an effective amount of (a) an agent that decreases the expression and / or activity of CCAAT / enhancer-binding protein beta (Cebpb); (b) an agent that decreases 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-inducer-obliterator 1 (Dido1).

[0036] In some embodiments, anti-tumor immunity in the individual is increased by at least 10% compared to anti-tumor immunity in the absence of the agent.

[0037] 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 beta (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-inducer-obliterator 1 (Dido1).

[0038] In some embodiments, the rate is in an individual's tumor or tissue.

[0039] In some embodiments, the proportion of mDCs in the individual is reduced by at least 10% compared to the proportion in the absence of the agent.

[0040] In another aspect, the present invention provides a method for reducing autoimmune activity 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 beta (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-inducer-obliterator 1 (Dido1).

[0041] In some embodiments, autoimmune activity in the individual is reduced by at least 10% compared to anti-tumor immunity in the absence of the agent.

[0042] In some embodiments, the inflammatory or autoimmune disease is a neurodegenerative disease, arthritis, allergy, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some embodiments, the neurodegenerative disease is MS, AD, ALS, or PD.

[0043] In some aspects, the agent is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid.

[0044] In some embodiments, the inhibitory nucleic acid is an ASO or an siRNA.

[0045] In some embodiments, the antigen-binding fragment is a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain.

[0046] In some embodiments, the antibody or antigen-binding fragment thereof binds to Cebpb, Traf2; and / or Dido1.

[0047] In some embodiments, the methods further comprise administering one or more additional agents to the individual.

[0048] In some embodiments, the method comprises: (a) detecting a gene encoding one of: 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, LO C100861784, Lrr1, Lrrc41, Map3k7, Mdm4, Mib1, Mkrn1, Mnat1, Naca, Nsmaf, Ogt, Pa2g 4, Pcif1, Ppp1r11, Prc1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah2, Taf3, T dpoz2, 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, Fbx o28, Fbxo3, Fbxw9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, Mlst8, Mtor, Nosip, Paf1, Pik3r4, Pparg, Ppp2r2 a, 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 to the individual;

[0049] In another aspect, the invention provides kits comprising (a) an agent that decreases the expression and / or activity of Cebpb; (b) an agent that decreases the expression and / or activity of Traf2; and / or (c) an agent that increases the expression and / or activity of Dido1 for treating an individual with cancer, an inflammatory disease, or an autoimmune disease by any one of the methods provided herein. In some aspects, the kits include a package insert containing instructions for administering the agent to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0050] In another aspect, the invention provides kits 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 for treating an individual with an inflammatory or autoimmune disease by any one of the methods provided herein. In some aspects, the kit includes a package insert containing instructions for administering the agent to an individual with an inflammatory or autoimmune disease.

[0051] In another aspect, the present invention provides a method for monitoring the response of an individual having cancer, an inflammatory disease, an autoimmune disease, or an infectious disease to treatment with (a) an agent that decreases the expression and / or activity of Cebpb; (b) an agent that decreases the expression and / or activity of Traf2; and / or (c) an agent that increases the expression and / or activity of Dido1, the method comprising: (i) determining the expression level of one or more of Cebpb, Traf2, and Dido1 in a biological sample obtained from the individual at a time point after administration of the agent; and (ii) comparing the expression level of one or more genes in the biological sample with a reference level, thereby monitoring the response of the individual to treatment with the agent.

[0052] In another aspect, the present invention provides a method for monitoring the response of an individual having an inflammatory disease, autoimmune disease, or infectious disease to treatment with (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 method comprising: (i) determining the expression level of one or more of Cebpb, Traf2, and Dido1 in a biological sample obtained from the individual at a time point after administration of the agent; and (ii) comparing the expression level of one or more genes in the biological sample with a reference level, thereby monitoring the response of the individual to treatment with the agent.

[0053] In some embodiments, 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 the individual prior to administration of the agent; (ii) the expression level of one or more genes in a reference population; (iii) a pre-assigned expression level for one or more genes; or (iv) the expression level of one or more genes in a biological sample obtained from the individual at an earlier time point after administration of the agent.

[0054] In some embodiments, (a) Cebpb expression and / or activity is increased in a biological sample obtained from the individual compared to a reference level; (b) Traf2 expression and / or activity is increased in a biological sample obtained from the individual compared to a reference level; and / or (c) Dido1 expression and / or activity is decreased in a biological sample obtained from the individual compared to a reference level, and the method further comprises administering one or more additional doses of an agent to the individual, wherein the agent decreases Cebpb expression and / or activity; decreases Traf2 expression and / or activity; and / or increases Dido1 expression and / or activity.

[0055] In some embodiments, (a) Cebpb expression and / or activity is decreased in a biological sample obtained from the individual compared to a reference level; (b) Traf2 expression and / or activity is decreased in a biological sample obtained from the individual compared to a reference level; and / or (c) Dido1 expression and / or activity is increased in a biological sample obtained from the individual compared to a reference level, and the method further comprises administering one or more additional doses of an agent to the individual, wherein the agent increases Cebpb expression and / or activity; increases Traf2 expression and / or activity; and / or decreases Dido1 expression and / or activity.

[0056] In another aspect, the present invention provides a method for treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method comprising administering to the individual an effective amount of a modulator of the interaction between (a) F-box and WD repeat domain-containing 11 (Fbxw11) and (b) nuclear factor kappa B subunit 1 (Nfkb1) or nuclear factor kappa B subunit 2 (Nfkb2).

[0057] In some embodiments, the individual has cancer and the modulator is an agent that increases the expression and / or activity of Fbxw11.

[0058] In some embodiments, the individual has an inflammatory or autoimmune disease and the modulator is an agent that decreases the expression and / or activity of Fbxw11.

[0059] In another aspect, the present invention provides a method for increasing the processing of Nfkb1 and / or Nfkb2 to their active forms, the method comprising contacting a cell capable of expressing Fbxw11 with an agent that increases the expression and / or activity of Fbxw11.

[0060] In some embodiments, the cell capable of expressing Fbxw11 is in an individual. In some embodiments, the individual has cancer.

[0061] In some embodiments, the levels of Nfkb1 and / or Nfkb2 in the active form are increased by at least 10% compared to the levels in the absence of the agent.

[0062] In another aspect, the present invention provides a method for reducing the processing of Nfkb1 and / or Nfkb2 to their active forms, the method comprising contacting a cell capable of expressing Fbxw11 with an agent that reduces the expression and / or activity of Fbxw11.

[0063] In some embodiments, the cell capable of expressing Fbxw11 is in an individual.

[0064] In some aspects, the individual has an inflammatory disease or an autoimmune disease.

[0065] In some embodiments, the levels of Nfkb1 and / or Nfkb2 in the active form are reduced by at least 10% compared to the levels in the absence of the agent.

[0066] 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.

[0067] In some embodiments, the individual has cancer.

[0068] 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.

[0069] In some aspects, the individual has an inflammatory disease or an autoimmune disease.

[0070] In some embodiments, the inflammatory or autoimmune disease is a neurodegenerative disease, arthritis, allergy, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some embodiments, the neurodegenerative disease is MS, AD, ALS, or PD.

[0071] In some embodiments, the agent is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid. In some embodiments, the inhibitory nucleic acid is an ASO or an siRNA.

[0072] In some embodiments, the antigen-binding fragment is a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain.

[0073] In some embodiments, the antibody or antigen-binding fragment thereof binds to Fbxw11.

[0074] In some embodiments, the methods further comprise administering one or more additional agents to the individual.

[0075] In some embodiments, the method comprises: (a) cloning the genes encoding 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, Lz tr1, 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, Arih 2, 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, Rbbp6, Rbck1, Rbx1, Rc3h1, Rela, Rlim, Rnf144a, Rnf3 1, 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 to the individual.

[0076] In another aspect, the invention provides kits comprising a modulator of the interaction between (a) Fbxw11 and (b) Nfkb1 or Nfkb2 for treating an individual with cancer, an inflammatory disease, or an autoimmune disease by any one of the methods provided herein. In some aspects, the kit comprises a package insert containing instructions for administering the modulator to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0077] In another aspect, the present invention provides 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) determining the expression level of activated forms of one or both of Nfkb1 and Nfkb2 in a biological sample obtained from the individual at a time point after administration of the modulator; and (ii) comparing the expression level of activated forms 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.

[0078] In some embodiments, the reference level is selected from the group consisting of: (i) the expression level of one or both genes in a biological sample obtained from the individual prior to administration of the modulator; (ii) the expression level of one or both genes in a reference population; (iii) a pre-assigned expression level for one or both genes; or (iv) the expression level of one or both genes in a biological sample obtained from the individual at an earlier time point after administration of the modulator.

[0079] In some aspects, the individual has cancer and the expression level of activated forms of one or both of Nfkb1 and Nfkb2 is decreased in a biological sample obtained from the individual compared to a reference level, and the method further comprises 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.

[0080] In some aspects, the individual has an inflammatory or autoimmune disease, and the expression level of activated forms of one or both of Nfkb1 and Nfkb2 is increased in a biological sample obtained from the individual compared to a baseline level, and the method further comprises administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that decreases the expression and / or activity of Fbxw11.

[0081] In another aspect, the present invention provides a method for treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method comprising detecting one or more of the following co-functional gene modules: (a) Aamp, Bop1, Cirh1a, Dcaf13, Grb2, Myc, Nle1, Nol10, Pak1ip1, Ptpn11, Rack1, Raf1, Rrp9, Taf5, Tbl3, Uhrf1, Utp15, Utp18, Vprbp, Wdr3, Wdr36, Wdr43, Wd (b) module M1, including r5, Wdr74, and Wdr75; (c) 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, Gm 10697, Gm9117, Gtf2h2, Gtf3c1, Hdac4, Hectd1, Ift122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23, Klhl3, Kmt2 b, LOC100861784, Lrr1, Lrrc41, Map3k7, Mdm4, Mib1, Mkrn1, Mnat1, Naca, Nsmaf, Ogt, Pa2g4, Pcif1, Ppp1r11, Prc1, Ring 1, module M2 containing 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)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, Mlst8, Mtor, Nosip, Paf1, Pik3r4, Pparg, (d) module M3, which contains 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; (e) module M4, which contains Cdc40, Ddx41, P module M4, including lrg1, Ppil2, Ppwd1, Prpf19, Prpf4, Sart1, Smu1, Snrnp40, and Wdr70; (e) module M5, including 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, and Kc module M5, including td13, 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) 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, Rbbp6, Rbck1, Rbx1, Rc3h1, Rela, Rlim, Rnf144a, administering to the individual an effective amount of a cell therapy comprising cells comprising alterations in at least two of the genes within one or more of module M6, including 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;

[0082] In another aspect, the present invention provides a method for treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method comprising: (a) detecting a gene in an individual having one of the following sets of genes: (a) 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, Myc, Naca, Ncl, Nf1, Nol10, Npm1, Ogt, Pa bpc1, Paf1, Plrg1, Pparg, Psap, Rack1, Raf1, Rheb, Rpl10, Rpl10a, Rpl11, Rpl12, Rpl13, Rpl13a, Rpl14, Rpl15, Rpl17, Rpl18, Rpl18a, Rpl19, R pl21, 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, Rps1 5, gene set 1 including Rps15a, Rps16, Rps17, Rps18, Rps19, Rps2, Rps20, Rps21, Rps23, Rps24, Rps25, Rps26, Rps27, Rps27a, Rps28, Rps29, Rps3, Rps3a1, Rps4x, Rps5, Rps6, Rps7, Rps8, Rps9, Rpsa, Rptor, Sgk1, Ssr4, Tab1, Taf5, Tpt1, Uhrf1, Uqcrh, Utp15, Wdr3, Wdr36, Wdr43, Wdr5, and Zbtb25;(b)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, Cxcl3, Cyb5a Dap, Dars, Dck, Ddb1, Ddit3, Egr2, Eif3f, Eif3i, Ep3 0, Esd, Fbxl5, Fbxw11, Gbe1, Gclm, Gdap10, Gm9840, Gss. Gstm1, H3f3b, Hmox1, Hvcn1, Il1f9, Inhba, Keap1, Lipa, Lmo4, Map3k7, Mcl1, Mcoln2, Met, Mgst2, Mmp12, Mmp19. Mmp8, Mylip, Nampt, Nedd8, Nf1, Npy, Nrp1, Nup43, Nupr1, Paf1, Pf4, Pgd, Phlda1, Pla2g7, Plet1, Ppfibp2, Prdx 1. Prdx6, Preb, Prkcb, Procr, Ptgr1, Ptpn1, Raf1, Rbx1, Rhob, Rnasel, Rnf128, Runx2, Sdc4, Sec13, Seh1l, Skp1 a, Slc43a2, Slc48a1, Slc7a11, Slpi, Smad2, Srxn1, Taldo1, Tarm1, Thbs1, Tlr2, Tlr4, Tma16, Tpm4, Traf2, and Traf 5, Traf6, Trip12, Tubb2a, Txnrd1, Ube2d3, Ube2n, Ubr5 Uchl1, Upf1, Wdr43, Wdr61, Zbtb17, and Zyx.(c)Acp5, Ankfy1, Arpc1b, Atp6v0d2, Bptf, Brap, C5ar1, Ccdc88a, Cd14, Cd36, Cd63, Cebpb, Ch d4, Clec4d, Clec5a, Cpd, Creg1, Ctsb, Ctsz, Cul3, Ddhd1, Dnmt3a, Egr2, Emb, F630028O10Rik, Fabp5, Fam46c, Fbxo42, Fcgr2b, Fn1, Foxo3, Fpr1, Ftl1, Gadd45a, Glrx, Gpnmb, Gpr84, Huwe1, Icam1, Id1, Il1f9, Kctd10, Keap1, Klhl6, Lcn2, Lgals1, Lgals3, Lgmn, Lipa, Lpcat2, Ly6c2, M arch6, Metrnl, Mgll, Mt1, Mtor, Myof, Naaa, Naca, Nf1, Paf1, Phlda1, Pid1, Pik3r4, Pld3, Ple t1, Plk2, Pou2f2, Pparg, Prdx5, Psap, Ptpn11, Rab3il1, Rela, Rfwd2, Rnase2a, S100a1, S100a 11, gene set 3 including S100a8, Saa3, Sdc3, Serpinb2, Slamf7, Snx18, Sod2, Spata13, Stap1, Strap, Tab1, Tceb2, Tgfbi, Thbs1, Trem1, Upf1, Upp1, Vat1, Wdfy3, Wfdc21,2010005H15Rik, and Zbtb25;(d)AC160336.1, Actb, Actg1, Ankfy1, Arhgdib, Bptf, Brap, Bri3, Ccr 2, Ccr5, Cd274, Cdkn1a, Cfl1, Chd4, Clec4a2, Cup, Crown1a, Cotl1, Cri p1, Cul1, Cul3, Dars, Ddhd1, Ddit3, Ear2, Eif3f, Eif3i, Ep300, Fbxw1 1. Flna, Gbp2, Gbp5, Grb2, Gtf3c1, H2-D1, H2-K1, Huwe1, Ifi27l2a, Il1 rn, Keap1, Klk1b1, Lcp1, Lgals1, Lpl, Lrr1, Lsp1, Malat1, Marksl1 Med8, Mgll, Mndal, Mtor, Naca, Nedd8, Nf1, Paf1, Pfn1, Pik3r4, Pten, P tma, Ptpn11, Rack1, Rela, Rnf20, Sdc4, Skp1a, Taf3, Taf5, Tlr4, Tmsb 4x, Ubb, Ube2i, Upf1, Vhl, Wdfy3, Wdr43, Wdr82, and Wfdc17.(e) Gene set 5 comprising AA467197, AW112010, Abcg1, Acod1, Bcl2a1b, Bcl2a1d, Cav1, Ccl17, Ccl3, Ccl4, Cd14, Cd200r1, Cd300lf, Cdkn1a, Cebpb, Cflar, Chd4, Clec4e, Clic4, Copa, Cpd, Cpeb4, Cul1, Cul3, Cxcl1, Cxcl2, Cxcl3, Ehd1, Ep300, Fam102b, Fam20c, Fbxw11, Gda, Gpr84, Hist1h1c, Hivep3, Ikbke, Ikbkg, Il12b, Il1a, Il1b, Il6, Ing3, Inhba, Kctd21, Klf4, Laptm5, Mafb, Malat1, Malt1, Marcks, Marcksl1, Marco, Met, Mtpn, Nabp1, Nedd8, Nfkb1, Nfkbiz, Nlrp3, Nrp2, Nup62, Ogt, Paf1, Plek, Plrg1, Ppfia3, Prpf19, Ptgs2, Ptx3, Rassf4, Rbx1, Rela, Rfwd2, Rnf31, Serpinb2, Sh3bp5, Skp1a, Slc7a11, 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)AA467197, Ahr, Akt1, Ankfy1, Axl, Bhlhe40, Bhlhe41, Btg1, Ccl17, Ccl22, Ccr2, Cd40, C d52, Cd74, Cebpb, Chd4, Clec4e, Clec4n, Clic4, Cst3, Cstf1, Ctsb, Ctsd, Cxcl16, Dcstamp, E gr2, Etv3, Fabp4, Fabp5, Fam20c, Fbxw7, Fbxw9, Foxo3, Fpr1, Fth1, Ftl1, Gbp2, Gbp5, Gm2a, G nb1, Gnb2, Grb2, Grk3, Gsk3b, H2-Aa, H2-Ab1, Hmox1, Igf1, Il4i1, Irf4, Itgax, Jak2, Jund, K Gene set 6 includes cmf1, Klhl6, Kmt2d, Lgals1, Lyz2, March6, Mgl2, Mmp12, Mtor, Myc, Ndufa4, 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)Abca1, Actb, Ambra1, Atf4, Atp5g1, Atp5j, Atp5j2, Bcl2a1b, Calm1, C fl1, Chd4, Copa, Copb2, Cotl1, Cox8a, Cul3, Cybb, Dbi, Ddit3, Eef1a1, Ei f3f, Eif3i, Fbxo28, Fcer1g, Gpx1, Grb2, H2-M2, H2afz, H3f3a, Il1rn, Inh ba, 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, which contains polymers 7;(h)Aamp, Acsl1, Ambra1, Arf4, Arih2, Atf4, Bop1 C1qb, Calr, Canx, Ccng1, Cdkn1a, Chd4, Cirh1a, Clec2d, Cup, Copb2, Cop e, Cpd, Ctss, Cul3, Dad1, Dap, Dcaf13, Ddit3, Ddx41, Dstn, Eif3f, Eif3i. Erp29, Fbxw7, Fth1, Ftl1, Gm9840, Grb2, Gtf3c1, Herpud1, Hif1a, Hnrnpa 3 Hsp90b1, Hspa5, Ift20, Keap1, Kmt2d, Krtcap2, Lgals3, Lrr1, Lyz2, Ma nf, Map3k7, Mthfd2, Mtor, Myc, Naca, Nedd8, Nf1, Nol10, Ostc, P4hb, Pdia3 Pdia4, Pdia6, Phgdh, Plrg1, Preb, Prpf19, Pten, Ptpn1, Rack1, Rbx1, Re la, Rpl22l1, Rpn1, Rps19, Rrp9, Sdf2l1, Sec11c, Sec13, Sec22b, Sec31a,S ec61b, Sec61g, Selenos, Serf2, Serp1, Sf3b5, Spcs2, Ssr3, Surf4, Syvn1 Tceal9, Tceb1, Tceb2, Timm13, Tpt1, Tram1, Trp53, Ube2f, Ufm1, Uqcrq; Gene set 8, including Utp15, Vcp, Vhl, Vprbp, Wdr36, Wdr43, Wdr5, Wdr74, Wdr75, and Xbp1; (i) 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, Fbxw11, Ffar2, Fpr2, Fyb, Gas7, Gm9840, Gnb2, Gpnmb, Grb2, G sk3b, Hmgcs1, Huwe1, Ifitm3, Il1f9, Itgam, Jun, Kctd12, Kctd5, Keap1, Klhdc4, Kmt2c, Kmt2d, Lgals1, Lgal s3, Lmna, Lmo4, Lrpap1, Ly6c2, Lztr1, Maf, March6, Mcemp1, Mmp12, Mmp13, Mmp8, Msr1, Mtor, Naaa, Naca, Nf1 , Nfkbiz, Npc2, Npy, Paf1, Pdpn, Pf4, Plet1, Pparg, Prkcd, Pten, Ptgs2, Ptpn1, Ptpn11, Ptprc, Ptx3, Rbbp5, Gene set 9 includes Rela, Rfwd2, 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)Acaca, Ak4, Aldoa, Aldoc, Anapc13, Anxa2, Arih2, Arnt, Basp1, Bnip3l, Bsg, C3ar 1, Ccl9, Cd52, Chil3, Copa, Cul2, Cul3, Cul5, Egr2, Eif3i, Eif4ebp1, Emilin2, Eno1 Ep300, Fam162a, Gapdh, Gbe1, Gpi1, Gsn, Herpud1, Hif1a, Higd1a, Hilpda, Hk1, Hk2, H mox1, Huwe1, Ier3, Kctd10, Klk1b1, Ldha, Lgals3, Lipa, Lmo4, Lpcat2, Lyz2, March6 Mif, Mt1, Mt2, Mtor, Myc, Ndufv3, Nf1, Pdk1, Pfkl, Pgam1, Pgk1, Pgm2, Pkm, Prdx1, Pre lid1, Ptpn1, Ptpn11, Rbpj, Rfwd2, Rilpl2, Rnase2a, Sacs, Scd2, Sdc3, Sdc4, Sec13 lamf9, Slc16a3, Slc2a1, Slc7a2, Smu1, Socs3, Strap, Tarm1, Tceb1, Tceb2, Tgm2, Tlr 4, Tpi1, Trf, Ube2f, Vhl, Vim, Wdr43, Wdr82, Wfdc17, and 2010005H15Rik.(k)AA467197, Apobec1, Apoe, C1qa, C1qb, C1qc, C3, Car4, Ccl22, Ccl3, Ccl4, Ccl6, Ccl9, Cd83, Cdc40, Cebpb, Ch25h, Chd4, Copa, Crebbp, Cul1, Ddh d1, Ddx41, Egr2, Eif3f, Eif3i, Ep300, Fam49a, Fbxw11, Fn1, Fnbp1l, Gadd45b, Hdac4, Icam1, Icosl, Id2, Ikbkg, Il1a, Il4i1, Inhba, Itgax, Itgb2, Kctd10, Klk1b11, Lpl, Maf, Marcks, Marcksl1, Med8, Met, Mmp12, Ms4a6c, Ms4a7, Mt2, Mycbp2, Naca, Nedd8, Nfkbia, Phlda1, Plaur, Plrg1, Pparg, P pfibp2, Prpf19, Ptpn1, Rassf4, Rfwd2, Ring1, Rnase2a, Rpl12, Scimp, Sec13, Skp1a, Slc43a2, Smu1, Sqstm1, Syk, Syvn1, Taf5l, Tceb2, Tmem176a, Gene set 11 includes Tmem176b, Tnfaip2, Traf3, Ufm1, Upp1, Wdr5, Wdr70, Wdr82, Wfdc17, Wfdc21, 0610012G03Rik, Zbtb7a, and Zyx; (l) Ambra1, Aplp2, Atp5g1, Atpif1, B2m, Ccdc88a, Chd4, Copa, Cyba, Ddit3, Ear2, Egr2, Eif3f, Eif3i, Eif5, Fcgrt, Grn, H2-M2, H2-Q6, Hint1, Id1, Ifi204, Itgal, Kctd12; Gene set 12 includes 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)Ankfy1, Anxa1, Anxa5, Aph1c, Brap, C3ar1, Ccnd2, Ccr1, Cd300lf, Cd38, Cd68, Cd9, Cdc27, Cdc40, Cebpb, Chd4, Chst11, Clec4e, Creb5, Cul1, Cul3, Cxcl3, Cyba, Dstn, Eif 3f, Eif3i, Emp1, Epha4, Fam102b, Fam46a, Fbxw11, Fn1, Foxo3, Ftl1, Furin, Gas7, Gdf1 5, Grb2, H2-K1, Huwe1, Icam1, Il7r, Inhba, Keap1, Klhdc4, Klk1b11, Lgals3, Lpl, Ly6c 2, gene set 13 including Lyz2, March6, Mbnl1, Mmp14, Mmp8, Ms4a7, Naca, Neat1, Nf1, Nrp2, Plin2, 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)AC160336.1, Adgre1, Adgre4, Adgrl2, Anxa1, B2m, C1qb, C3, Car4, Ccdc88a, Ccl6, C d52, 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, Marcks, Mcub, Med8, Gene set 14 includes 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)AC160336.1, Adgre1, Ahnak, Alcam, Aprt, Bcl2l11, Blvrb, Brap, Bub3, C1qb, C1qc, C3ar 1, 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, Huw e1, Igf1, Kat6a, Kctd12b, Kdm5c, Keap1, Kmt2d, Lst1, Mmp14, Mpeg1, Myc, Naca, P2ry14, Paf1, Pi administering to the individual an effective amount of a cell therapy comprising cells comprising alterations in at least two of the genes within one or more of gene set 15, including rb, Plrg1, Pou2f2, Pparg, Ppil2, Ppwd1, Prkcd, Prpf19, Prpf4, Ptpn1, Ptpn18, Rack1, Rbbp5, Rnf20, Rnf40, Rnf7, Rps27l, Sat1, Serpinb2, Smu1, Socs3, Spp1, Taf5, Tank, Tceb1, Tceb2, Tgm2, Tnfsf15, Traf2, Trem2, Tyrobp, Ufm1, Vcan, Wdr1, Wdr33, Wdr43, Wdr5, Wdr61, Wdr70, Wdr82, Wfdc21, and Ybx1;

[0083] In some aspects, the cell therapy is dendritic cell therapy, macrophage cell 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.

[0084] In another aspect, the invention provides a kit comprising a cell therapy comprising cells comprising alterations in at least two of the genes within one or more of the co-functional gene modules, for treating an individual with cancer, an inflammatory disease, or an autoimmune disease according to the methods provided herein.

[0085] In another aspect, the invention provides kits containing reagents for modifying cells to contain alterations in at least two of the genes within one or more of the co-functional gene modules for treating an individual with cancer, an inflammatory disease, or an autoimmune disease according to the methods provided herein.

[0086] In some embodiments, the kit includes a package insert containing instructions for administering the agent to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0087] In another aspect, the invention provides kits comprising cell therapies comprising cells comprising alterations in at least two of the genes within one or more of the above gene sets for treating an individual with cancer, an inflammatory disease, or an autoimmune disease according to the methods provided herein.

[0088] In another aspect, the invention provides kits containing reagents for modifying cells to contain alterations in at least two of the genes in one or more of the above gene sets for treating an individual with cancer, an inflammatory disease, or an autoimmune disease by the methods provided herein.

[0089] In some embodiments, the kit includes a package insert containing instructions for administering the agent to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0090] In another aspect, the present invention provides the following co-functional gene modules: (a) module M1, including 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, including 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; go2, 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, R module M2, which includes nf20, 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)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, Mlst8, Mtor, Nosip, Paf1, Pik3r4, Pparg, (d) module M3, which contains 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; (e) module M4, which contains Cdc40, Ddx41, P module M4, including lrg1, Ppil2, Ppwd1, Prpf19, Prpf4, Sart1, Smu1, Snrnp40, and Wdr70; (e) module M5, including 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, and Kc module M5, including td13, 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) 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, Rbbp6, Rbck1, Rbx1, Rc3h1, Rela, Rlim, Rnf144 a, 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;

[0091] In another aspect, the present invention provides the following gene sets: (a) 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, Hsp90 ab1, Hspa5, Hspa8, Il1rn, Laptm5, Lhfpl2, March6, Ms4a7, Mtor, Myc, Naca, Ncl, Nf1, Nol10, Npm1, Ogt, Pabpc1, Paf1, Plrg1, Pparg, Psa p, Rack1, Raf1, Rheb, Rpl10, Rpl10a, Rpl11, Rpl12, Rpl13, Rpl13a, Rpl14, Rpl15, Rpl17, Rpl18, Rpl18a, Rpl19, Rpl21, Rpl22, Rpl22l1, R pl23, Rpl23a, Rpl24, Rpl26, Rpl27a, Rpl28, Rpl29, Rpl3, Rpl30, Rpl31, Rpl32, Rpl34, Rpl35, Rpl35a, Rpl36, Rpl36a, Rpl37, Rpl37a, Rp l38, Rpl39, Rpl4, Rpl41, Rpl5, Rpl6, Rpl7, Rpl7a, Rpl8, Rpl9, Rplp0, Rplp1, Rplp2, Rps10, Rps11, Rps12, Rps13, Rps14, Rps15, Rps15a, R Gene set 1 includes ps16, Rps17, Rps18, Rps19, Rps2, Rps20, Rps21, Rps23, Rps24, Rps25, Rps26, Rps27, Rps27a, Rps28, Rps29, Rps3, Rps3a1, Rps4x, Rps5, Rps6, Rps7, Rps8, Rps9, Rpsa, Rptor, Sgk1, Ssr4, Tab1, Taf5, Tpt1, Uhrf1, Uqcrh, Utp15, Wdr3, Wdr36, Wdr43, Wdr5, and Zbtb25;(b)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, Cxcl3, Cyb5a Dap, Dars, Dck, Ddb1, Ddit3, Egr2, Eif3f, Eif3i, Ep3 0, Esd, Fbxl5, Fbxw11, Gbe1, Gclm, Gdap10, Gm9840, Gss. Gstm1, H3f3b, Hmox1, Hvcn1, Il1f9, Inhba, Keap1, Lipa, Lmo4, Map3k7, Mcl1, Mcoln2, Met, Mgst2, Mmp12, Mmp19. Mmp8, Mylip, Nampt, Nedd8, Nf1, Npy, Nrp1, Nup43, Nupr1, Paf1, Pf4, Pgd, Phlda1, Pla2g7, Plet1, Ppfibp2, Prdx 1. Prdx6, Preb, Prkcb, Procr, Ptgr1, Ptpn1, Raf1, Rbx1, Rhob, Rnasel, Rnf128, Runx2, Sdc4, Sec13, Seh1l, Skp1 a, Slc43a2, Slc48a1, Slc7a11, Slpi, Smad2, Srxn1, Taldo1, Tarm1, Thbs1, Tlr2, Tlr4, Tma16, Tpm4, Traf2, and Traf 5, Traf6, Trip12, Tubb2a, Txnrd1, Ube2d3, Ube2n, Ubr5 Uchl1, Upf1, Wdr43, Wdr61, Zbtb17, and Zyx.(c)Acp5, Ankfy1, Arpc1b, Atp6v0d2, Bptf, Brap, C5ar1, Ccdc88a, Cd14, Cd36, Cd63, Cebpb, Ch d4, Clec4d, Clec5a, Cpd, Creg1, Ctsb, Ctsz, Cul3, Ddhd1, Dnmt3a, Egr2, Emb, F630028O10Rik, Fabp5, Fam46c, Fbxo42, Fcgr2b, Fn1, Foxo3, Fpr1, Ftl1, Gadd45a, Glrx, Gpnmb, Gpr84, Huwe1, Icam1, Id1, Il1f9, Kctd10, Keap1, Klhl6, Lcn2, Lgals1, Lgals3, Lgmn, Lipa, Lpcat2, Ly6c2, M arch6, Metrnl, Mgll, Mt1, Mtor, Myof, Naaa, Naca, Nf1, Paf1, Phlda1, Pid1, Pik3r4, Pld3, Ple t1, Plk2, Pou2f2, Pparg, Prdx5, Psap, Ptpn11, Rab3il1, Rela, Rfwd2, Rnase2a, S100a1, S100a 11, gene set 3 including S100a8, Saa3, Sdc3, Serpinb2, Slamf7, Snx18, Sod2, Spata13, Stap1, Strap, Tab1, Tceb2, Tgfbi, Thbs1, Trem1, Upf1, Upp1, Vat1, Wdfy3, Wfdc21,2010005H15Rik, and Zbtb25;(d)AC160336.1, Actb, Actg1, Ankfy1, Arhgdib, Bptf, Brap, Bri3, Ccr 2, Ccr5, Cd274, Cdkn1a, Cfl1, Chd4, Clec4a2, Cup, Crown1a, Cotl1, Cri p1, Cul1, Cul3, Dars, Ddhd1, Ddit3, Ear2, Eif3f, Eif3i, Ep300, Fbxw1 1. Flna, Gbp2, Gbp5, Grb2, Gtf3c1, H2-D1, H2-K1, Huwe1, Ifi27l2a, Il1 rn, Keap1, Klk1b1, Lcp1, Lgals1, Lpl, Lrr1, Lsp1, Malat1, Marksl1 Med8, Mgll, Mndal, Mtor, Naca, Nedd8, Nf1, Paf1, Pfn1, Pik3r4, Pten, P tma, Ptpn11, Rack1, Rela, Rnf20, Sdc4, Skp1a, Taf3, Taf5, Tlr4, Tmsb 4x, Ubb, Ube2i, Upf1, Vhl, Wdfy3, Wdr43, Wdr82, and Wfdc17.(e) Gene set 5 comprising AA467197, AW112010, Abcg1, Acod1, Bcl2a1b, Bcl2a1d, Cav1, Ccl17, Ccl3, Ccl4, Cd14, Cd200r1, Cd300lf, Cdkn1a, Cebpb, Cflar, Chd4, Clec4e, Clic4, Copa, Cpd, Cpeb4, Cul1, Cul3, Cxcl1, Cxcl2, Cxcl3, Ehd1, Ep300, Fam102b, Fam20c, Fbxw11, Gda, Gpr84, Hist1h1c, Hivep3, Ikbke, Ikbkg, Il12b, Il1a, Il1b, Il6, Ing3, Inhba, Kctd21, Klf4, Laptm5, Mafb, Malat1, Malt1, Marcks, Marcksl1, Marco, Met, Mtpn, Nabp1, Nedd8, Nfkb1, Nfkbiz, Nlrp3, Nrp2, Nup62, Ogt, Paf1, Plek, Plrg1, Ppfia3, Prpf19, Ptgs2, Ptx3, Rassf4, Rbx1, Rela, Rfwd2, Rnf31, Serpinb2, Sh3bp5, Skp1a, Slc7a11, 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)AA467197, Ahr, Akt1, Ankfy1, Axl, Bhlhe40, Bhlhe41, Btg1, Ccl17, Ccl22, Ccr2, Cd40, C d52, Cd74, Cebpb, Chd4, Clec4e, Clec4n, Clic4, Cst3, Cstf1, Ctsb, Ctsd, Cxcl16, Dcstamp, E gr2, Etv3, Fabp4, Fabp5, Fam20c, Fbxw7, Fbxw9, Foxo3, Fpr1, Fth1, Ftl1, Gbp2, Gbp5, Gm2a, G nb1, Gnb2, Grb2, Grk3, Gsk3b, H2-Aa, H2-Ab1, Hmox1, Igf1, Il4i1, Irf4, Itgax, Jak2, Jund, K Gene set 6 includes cmf1, Klhl6, Kmt2d, Lgals1, Lyz2, March6, Mgl2, Mmp12, Mtor, Myc, Ndufa4, 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)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, Inhba, Keap1, Km gene set 7, including t2d, 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)Aamp, Acsl1, Ambra1, Arf4, Arih2, Atf4, Bop1, C1qb, Calr, Canx, Ccng1, Cdkn1a, Chd4, Cirh1a, Cl ec2d, Copa, Copb2, Cope, Cpd, Ctss, Cul3, Dad1, Dap, Dcaf13, Ddit3, Ddx41, Dstn, Eif3f, Eif3i, Erp2 9. Fbxw7, Fth1, Ftl1, Gm9840, Grb2, Gtf3c1, Herpud1, Hif1a, Hnrnpa3, Hsp90b1, Hspa5, Ift20, Keap1 Kmt2d, Krtcap2, Lgals3, Lrr1, Lyz2, Manf, Map3k7, Mthfd2, Mtor, Myc, Naca, Nedd8, Nf1, Nol10, Ostc P4hb, Pdia3, Pdia4, Pdia6, Phgdh, Plrg1, Preb, Prpf19, Pten, Ptpn1, Rack1, Rbx1, Rela, Rpl22l1 pn1, Rps19, Rrp9, Sdf2l1, Sec11c, Sec13, Sec22b, Sec31a, Sec61b, Sec61g, Selenos, Serf2, Serp1, Sf 3b5, Spcs2, Ssr3, Surf4, Syvn1, Tceal9, Tceb1, Tceb2, Timm13, Tpt1, Tram1, Trp53, Ube2f, Ufm1, Uqc rq, Utp15, Vcp, Vhl, Vprbp, Wdr36, Wdr43, Wdr5, Wd r74, Wdr75, and Xbp1 have been isolated from factor 8; (i)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, Fbxw11, Ffar2, Fpr2, Fyb, Gas7, Gm9840, Gnb2, Gpnmb, Grb2, Gsk3b, Hmgcs1, Huwe1, Ifitm3, Il1f9, Itgam, Jun, Kctd12, Kct d5, Keap1, Klhdc4, Kmt2c, Kmt2d, Lgals1, Lgals3, Lmna, Lmo4, Lrpap1, Ly6c2, Lztr1, Maf, March 6, Mcemp1, Mmp12, Mmp13, Mmp8, Msr1, Mtor, Naaa, Naca, Nf1, Nfkbiz, Npc2, Npy, Paf1, Pdpn, Pf4, Plet1, Pparg, Prkcd, Pten, Ptgs2, Ptpn1, Ptpn11, Ptprc, Ptx3, Rbbp5, Rela, Rfwd2, Rheb, Rptor , gene set 9 including 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)Acaca, Ak4, Aldoa, Aldoc, Anapc13, Anxa2, Arih2, Arnt, Basp1, Bnip3l, Bsg, C3ar 1, Ccl9, Cd52, Chil3, Copa, Cul2, Cul3, Cul5, Egr2, Eif3i, Eif4ebp1, Emilin2, Eno1 Ep300, Fam162a, Gapdh, Gbe1, Gpi1, Gsn, Herpud1, Hif1a, Higd1a, Hilpda, Hk1, Hk2, H mox1, Huwe1, Ier3, Kctd10, Klk1b1, Ldha, Lgals3, Lipa, Lmo4, Lpcat2, Lyz2, March6 Mif, Mt1, Mt2, Mtor, Myc, Ndufv3, Nf1, Pdk1, Pfkl, Pgam1, Pgk1, Pgm2, Pkm, Prdx1, Pre lid1, Ptpn1, Ptpn11, Rbpj, Rfwd2, Rilpl2, Rnase2a, Sacs, Scd2, Sdc3, Sdc4, Sec13 lamf9, Slc16a3, Slc2a1, Slc7a2, Smu1, Socs3, Strap, Tarm1, Tceb1, Tceb2, Tgm2, Tlr 4, Tpi1, Trf, Ube2f, Vhl, Vim, Wdr43, Wdr82, Wfdc17, and 2010005H15Rik.(k)AA467197, Apobec1, Apoe, C1qa, C1qb, C1qc, C3, Car4, Ccl22, Ccl3, Ccl4, Ccl6, Ccl9, Cd83, Cdc40, Cebpb, Ch25h, Chd4, Copa, Crebbp, Cul1, Ddh d1, Ddx41, Egr2, Eif3f, Eif3i, Ep300, Fam49a, Fbxw11, Fn1, Fnbp1l, Gadd45b, Hdac4, Icam1, Icosl, Id2, Ikbkg, Il1a, Il4i1, Inhba, Itgax, Itgb2, Kctd10, Klk1b11, Lpl, Maf, Marcks, Marcksl1, Med8, Met, Mmp12, Ms4a6c, Ms4a7, Mt2, Mycbp2, Naca, Nedd8, Nfkbia, Phlda1, Plaur, Plrg1, Pparg, P pfibp2, Prpf19, Ptpn1, Rassf4, Rfwd2, Ring1, Rnase2a, Rpl12, Scimp, Sec13, Skp1a, Slc43a2, Smu1, Sqstm1, Syk, Syvn1, Taf5l, Tceb2, Tmem176a, Gene set 11 includes Tmem176b, Tnfaip2, Traf3, Ufm1, Upp1, Wdr5, Wdr70, Wdr82, Wfdc17, Wfdc21, 0610012G03Rik, Zbtb7a, and Zyx; (l) Ambra1, Aplp2, Atp5g1, Atpif1, B2m, Ccdc88a, Chd4, Copa, Cyba, Ddit3, Ear2, Egr2, Eif3f, Eif3i, Eif5, Fcgrt, Grn, H2-M2, H2-Q6, Hint1, Id1, Ifi204, Itgal, Kctd12; Gene set 12 includes 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)Ankfy1, Anxa1, Anxa5, Aph1c, Brap, C3ar1, Ccnd2, Ccr1, Cd300lf, Cd38, Cd68, Cd9, Cdc27, Cdc40, Cebpb, Chd4, Chst11, Clec4e, Creb5, Cul1, Cul3, Cxcl3, Cyba, Dstn, Eif 3f, Eif3i, Emp1, Epha4, Fam102b, Fam46a, Fbxw11, Fn1, Foxo3, Ftl1, Furin, Gas7, Gdf1 5, Grb2, H2-K1, Huwe1, Icam1, Il7r, Inhba, Keap1, Klhdc4, Klk1b11, Lgals3, Lpl, Ly6c 2, gene set 13 including Lyz2, March6, Mbnl1, Mmp14, Mmp8, Ms4a7, Naca, Neat1, Nf1, Nrp2, Plin2, 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)AC160336.1, Adgre1, Adgre4, Adgrl2, Anxa1, B2m, C1qb, C3, Car4, Ccdc88a, Ccl6, C d52, 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, Marcks, Mcub, Med8, Gene set 14 includes 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)AC160336.1, Adgre1, Ahnak, Alcam, Aprt, Bcl2l11, Blvrb, Brap, Bub3, C1qb, C1qc, C3ar 1, 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, Hu we1, Igf1, Kat6a, Kctd12b, Kdm5c, Keap1, Kmt2d, Lst1, Mmp14, Mpeg1, Myc, Naca, P2ry14, Paf1, P The present invention provides a genetically modified isolated cell comprising an alteration in at least two of the genes within one or more of gene set 15, the gene set 15 including irb, Plrg1, Pou2f2, Pparg, Ppil2, Ppwd1, Prkcd, Prpf19, Prpf4, Ptpn1, Ptpn18, Rack1, Rbbp5, Rnf20, Rnf40, Rnf7, Rps27l, Sat1, Serpinb2, Smu1, Socs3, Spp1, Taf5, Tank, Tceb1, Tceb2, Tgm2, Tnfsf15, Traf2, Trem2, Tyrobp, Ufm1, Vcan, Wdr1, Wdr33, Wdr43, Wdr5, Wdr61, Wdr70, Wdr82, Wfdc21, and Ybx1;

[0092] In some embodiments, at least one of the alterations is a loss-of-function alteration.

[0093] In some embodiments, at least one of the alterations is a gain-of-function alteration.

[0094] In some embodiments, the genetically modified isolated cells comprise loss-of-function alterations in one, two, or all three of Ldb2, Rnf165, and Traf2, hi some embodiments, the loss-of-function alterations are knockout (KO) mutations.

[0095] In some embodiments, the genetically modified isolated cells comprise a gain-of-function alteration in CCR7. In some embodiments, the gain-of-function alteration is overexpression.

[0096] In another aspect, the present invention provides a method for identifying a modulator of the interaction between F-box and WD repeat domain-containing 11 (Fbxw11) and nuclear factor kappa B subunit 1 (Nfkb1) or nuclear factor kappa B subunit 2 (Nfkb2), the method comprising: (a) providing a candidate modulator; (b) binding of Fbxw11 to Nfkb1 or Nfkb2 in the presence or absence of the candidate modulator under conditions that allow binding of Fbxw11 to Nfkb1 or Nfkb2. (c) contacting Fbxw11 with Nfkb1 or Nfkb2; (d) measuring the binding of Fbxw11 to Nfkb1 or Nfkb2, wherein an increase or decrease in binding in the presence of a candidate modulator compared 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.

[0097] In another aspect, the present invention provides a method for identifying a modulator of downstream activity of Fbxw11, 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 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 modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of Fbxw11.

[0098] In another aspect, the present invention provides a method for identifying a modulator of downstream activity of Nfkb1 or Nfkb2, the method comprising: (a) providing a candidate modulator; (b) contacting Nfkb1 or Nfkb2 with Fbxw11 in the presence or absence of the candidate modulator 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 downstream activity in the presence of the candidate modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of downstream activity of Nfkb1 or Nfkb2.

[0099] In some embodiments, the increase or decrease in binding is at least 50% as measured by surface plasmon resonance, biolayer interferometry, or enzyme-linked immunosorbent assay (ELISA).

[0100] In some embodiments, the modulator is an inhibitor of Fbxw11 or downstream activity of Nfkb1 or Nfkb2.

[0101] In some aspects, the change in downstream activity is an increase in the amount, intensity, or duration of the downstream activity.

[0102] In some aspects, the change in downstream activity is a decrease in the amount, intensity, or duration of the downstream activity.

[0103] In some embodiments, the modulator is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid. In some embodiments, the inhibitory nucleic acid is an ASO or siRNA.

[0104] In some embodiments, the antigen-binding fragment is a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain.

[0105] In some embodiments, the antibody or antigen-binding fragment thereof binds to Fbxw11.

[0106] In some embodiments, the antibody or antigen-binding fragment thereof binds to Nfkb1 or Nfkb2.

[0107] In some aspects, the downstream activity is activation of an immune response.

[0108] In another aspect, the present invention provides a method for preventing or treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method comprising administering to the individual an effective amount of a modulator identified by any one of the methods provided herein, thereby treating the individual.

[0109] 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.

[0110] In another aspect, the present invention provides a method for treating an inflammatory or autoimmune disease 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 reduced in the presence of the modulator.

[0111] In another aspect, the invention provides a method for the preparation of a protein comprising RING finger and WD repeat domain 2 (Rfwd2) and a cluster selected from forkhead box L2 (Foxl2), JunD, WD repeat domain 2 (Wdr82); E1A-binding protein p300 (Ep300); anaphase-promoting complex subunit 13 (Anapc13); Cullin 2 (Cul2); Cullin 5 (Cul5); HECT, UBA, and WWE domain-containing E3 ubiquitin protein ligase 1 (Huwe1); CREB-binding protein (Crebbp); S-phase kinase-associated protein 1 (Skp1a); developmentally downregulated gene expressed in neural precursor cells 8 (Nedd8); Cullin 1 (Cul1); and WD repeat domain 5 (Wdr5). Provided is a method for identifying a modulator of the interaction between an Rfwd2 and an Erie protein, the method comprising: (a) providing a candidate modulator; (b) contacting Rfwd2 with the query protein in the presence or absence of the candidate modulator under conditions that allow binding of Rfwd2 to the query protein; and (c) measuring binding of Rfwd2 to the query protein, wherein an increase or decrease in binding in the presence of the candidate modulator compared to binding in the absence of the candidate modulator identifies the candidate modulator as a modulator of the interaction between Rfwd2 and the query protein.

[0112] In another aspect, the present invention provides a method for identifying a modulator of a downstream activity of Rfwd2, the method comprising: (a) providing a candidate modulator; (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 modulator under conditions that allow binding of Rfwd2 to the query protein; and (c) measuring the downstream activity of Rfwd2, wherein a change in the downstream activity in the presence of the candidate modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of Rfwd2.

[0113] In another aspect, the present invention provides a method for identifying a modulator of a 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 modulator; (b) contacting the query protein with Rfwd2 in the presence or absence of the candidate modulator under conditions that allow binding of the query protein 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 modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of the query protein.

[0114] In some embodiments, the increase or decrease in binding is at least 50% as measured by surface plasmon resonance, biolayer interferometry, or enzyme-linked immunosorbent assay (ELISA).

[0115] In some embodiments, the modulator is an inhibitor of a downstream activity of Rfwd2 or the query protein.

[0116] In some aspects, the change in downstream activity is an increase in the amount, intensity, or duration of the downstream activity.

[0117] In some aspects, the change in downstream activity is a decrease in the amount, intensity, or duration of the downstream activity.

[0118] In some embodiments, the modulator is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid. In some embodiments, the inhibitory nucleic acid is an ASO or siRNA.

[0119] In some embodiments, the antigen-binding fragment is a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain.

[0120] In some embodiments, the antibody or antigen-binding fragment thereof binds to Rfwd2.

[0121] In some aspects, the antibody or antigen-binding fragment thereof binds to the query protein.

[0122] In some aspects, the downstream activity is dendritic cell or macrophage migration.

[0123] In another aspect, the present invention provides a method for preventing or treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method comprising administering to the individual an effective amount of a modulator identified by the methods provided herein, thereby treating the individual.

[0124] In another aspect, the invention provides a method for treating an inflammatory or autoimmune disease 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 reduced in the presence of the modulator.

[0125] In another aspect, the 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.

[0126] In another aspect, the invention provides kits 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 treating an individual with cancer, an inflammatory disease, or an autoimmune disease according to the methods provided herein. In some aspects, the kit comprises a package insert containing instructions for administering the modulator to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0127] In another aspect, the present invention provides a method for identifying a modulator of the interaction between a protein complex comprising tyrosine-protein phosphatase non-receptor type 11 (Ptpn11) and a Ring finger and WD repeat domain 2 (Rfwd2) and a CCAAT enhancer-binding protein (Cebp) family transcription factor, the method comprising: (a) providing a candidate modulator; (b) contacting the protein complex with the Cebp family transcription factor in the presence or absence of the candidate modulator under conditions that allow binding of Rfwd2 to a query protein; and (c) measuring binding of the protein complex to the Cebp family transcription factor, wherein an increase or decrease in binding in the presence of the candidate modulator compared to binding in the absence of the candidate modulator identifies the candidate modulator as a modulator of the interaction between the protein complex and the Cebp family transcription factor.

[0128] In another aspect, the present invention provides a method for identifying a modulator of a downstream activity of a protein complex comprising Ptpn11 and Rfwd2, the method comprising: (a) providing a candidate modulator; (b) contacting the protein complex with a Cebp family transcription factor in the presence or absence of the candidate modulator under conditions that allow binding of the protein complex 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 modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of the protein complex.

[0129] In another aspect, the present invention provides a method for identifying a modulator of a downstream activity of a Cebp family transcription factor, the method comprising: (a) providing a candidate modulator; (b) contacting the Cebp family transcription factor with a protein complex comprising Ptpn11 and Rfwd2 in the presence or absence of the candidate modulator under conditions that allow 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 the downstream activity in the presence of the candidate modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of the query protein.

[0130] In some embodiments, the increase or decrease in binding is at least 50% as measured by surface plasmon resonance, biolayer interferometry, or enzyme-linked immunosorbent assay (ELISA).

[0131] In some embodiments, the modulator is an inhibitor of a protein complex or downstream activity of a Cebp family transcription factor.

[0132] In some aspects, the change in downstream activity is an increase in the amount, intensity, or duration of the downstream activity.

[0133] In some aspects, the change in downstream activity is a decrease in the amount, intensity, or duration of the downstream activity.

[0134] In some embodiments, the modulator is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid. In some embodiments, the inhibitory nucleic acid is an ASO or siRNA.

[0135] In some embodiments, the antigen-binding fragment is a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain.

[0136] In some aspects, the antibody or antigen-binding fragment thereof binds to the protein complex.

[0137] In some embodiments, the antibody or antigen-binding fragment thereof binds to a Cebp family transcription factor.

[0138] In another aspect, the invention provides a method for preventing or treating a disease or disorder associated with antigen presenting cells (APCs) and / or inflammation in an individual, the method comprising administering to the individual an effective amount of a modulator of a gene of Table 1 or Table 2, thereby treating the individual.

[0139] In some aspects, the modulator modulates the expression of a gene, hi some aspects, the modulator modulates the expression or activity of a protein encoded by a gene.

[0140] In some embodiments, a modulator causes a change in the downstream activity of a protein encoded by a gene of Table 1 or Table 2 in the presence of the modulator compared to the downstream activity in the absence of the modulator.

[0141] In some embodiments, the modulator is an inhibitor of the downstream activity of a gene of Table 1 or Table 2.

[0142] In some aspects, the change in downstream activity is a decrease in the amount, intensity, or duration of the downstream activity.

[0143] In some embodiments, the modulator is an activator of a downstream activity of a gene of Table 1 or Table 2.

[0144] In some aspects, the change in downstream activity is an increase in the amount, intensity, or duration of the downstream activity.

[0145] In some embodiments, the modulator is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid. In some embodiments, the inhibitory nucleic acid is an ASO or siRNA.

[0146] In some embodiments, the antigen-binding fragment is a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain.

[0147] In some embodiments, the antibody or antigen-binding fragment thereof binds to a protein encoded by a gene in Table 1 or Table 2.

[0148] In some embodiments, the disease or disorder associated with APCs and / or inflammation is a neurodegenerative disease, arthritis, allergy, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or blastic plasmacytoma dendritic cell neoplasm. In some embodiments, the neurodegenerative disease is MS, AD, ALS, or PD.

[0149] In some embodiments, the APC is a DC, a macrophage, or a glial cell. In some embodiments, the glial cell is a microglial cell, an astrocyte, or an oligodendrocyte. In some embodiments, the APC is a DC.

[0150] In another aspect, the invention provides kits comprising a modulator of a gene in Table 1 or Table 2 for treating an individual having a disease or disorder associated with APCs and / or inflammation according to the methods provided herein. In some aspects, the kit comprises a package insert comprising instructions for administering the modulator to an individual having a disease or disorder associated with APCs and / or inflammation.

[0151] In another aspect, the invention provides methods of monitoring the response of an individual having a disease or disorder associated with APCs and / or inflammation to treatment with a modulator of a gene of Table 1 or Table 2, the method comprising: (a) determining the expression level of the gene of Table 1 or Table 2 in a biological sample obtained from the individual at a time after administration of the modulator; and (b) comparing the expression level of the gene of Table 1 or Table 2 in the biological sample to a reference level, thereby monitoring the response of the individual to treatment with the modulator. In some aspects, 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 administration of the modulator; (ii) the expression level of the gene in a reference population; (iii) a pre-assigned expression level for the gene; or (iv) the expression level of the gene in a biological sample obtained from the individual at an earlier time after administration of the modulator.

[0152] In some embodiments, the expression level of a gene of Table 1 or Table 2 is decreased in a biological sample obtained from the individual compared to a reference level, and the method further comprises administering to the individual one or more additional doses of a modulator, wherein the modulator is an agent that increases expression and / or activity of a gene of Table 1 or Table 2.

[0153] In some embodiments, the expression level of a gene of Table 1 or Table 2 is increased in a biological sample obtained from the individual relative to a reference level, and the method further comprises administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that decreases expression and / or activity of a gene of Table 1 or Table 2. [Brief explanation of the drawings]

[0154] [Figure 1A]Figure 1. Schematic diagram showing the design of a large-scale Perturb-Seq screen to assess the function of E3 ligases in the response to lipopolysaccharide (LPS) in bone marrow-derived dendritic cells (BMDCs). Top row: experimental flow. Middle row: Perturb-Seq vector design. Bottom row: exemplary E3 ligases and members of complexes known to regulate different processes. [Figure 1B-C] Figure 1B is a schematic illustrating key features of the PerturbDecode workflow. The complete workflow is shown in Figure 8E. KO: knockout; PPI: protein-protein interaction; TF: transcription factor. Figure 1C is a Uniform Manifold Approximation and Projection (UMAP) showing profiles of 519,535 perturbed single cells, shaded by cluster membership. [Figure 1D-H] Figure 1D is a UMAP showing 519,535 cell profiles shaded by the signature score of type 2 dendritic cell (DC2)-like cell types. Figure 1E is a UMAP showing 519,535 cell profiles shaded by the signature score of regulatory macrophage (MReg)-like cell types. Figure 1F is a UMAP showing 519,535 cell profiles shaded by the signature score of type 1 dendritic cell (DC1)-like cell types. Figure 1G is a UMAP showing 519,535 cell profiles shaded by cell cycle phase. Figure 1H is a UMAP showing 519,535 cell profiles shaded by the difference in macrophage versus dendritic cell (DC) signature scores (DC maturation). [Figure 1I] Heatmap showing odds ratios (shaded bars) of significant (false discovery rate (FDR) < 0.15, one-sided Fisher's exact test) enrichment (^) or depletion (v) of guides targeting perturbed genes (rows) in each major cell subset (columns) in the Perturb-Seq screen. Mac: macrophages. [Figure 1J]Paired tables showing a summary of enrichment (^) and depletion (v) of guides targeting key proteins within the major subsets (left table) and DC2 subtypes (right table), shaded by E3 family type and grouped by complex. ULD: ubiquitin-like domain; DUB: deubiquitinase; NS: not significant. [Figure 2A] Pie chart showing the proportion of 329 significant regulators (influential perturbed genes) in each of the indicated E3 family member types (left) and scatter plot showing UMAP embeddings of the regulatory profiles of the 329 regulators (KO genes), shaded by module membership. DUB: deubiquitinase; ULD: ubiquitin-like domain. [Figure 2B] Scatterplot showing UMAP embeddings of the regulated profiles of the 1,041 affected genes, shaded by membership in gene programs (GPs) 1-11. [Figure 2C] A set of regulation matrices. Top left: Regulation matrix (beta) showing the regulatory effect size of perturbing each of 329 genes (rows) on the expression of each of 1,041 affected genes (columns). Shading indicates induction / repression in response to perturbation (KO) compared to control cells. Black horizontal and vertical lines delineate co-functional modules and co-regulated programs, respectively. Top right: Regulation matrix showing co-functional modules. Covariance between regulatory profiles in beta of perturbing each of 329 genes. Genes are clustered by module (as in Figure 2A; shading codes are shown above and to the right). Bottom: Regulation matrix showing co-regulated programs. Covariance between regulatory profiles in beta of the effect on the expression of each of 1,041 genes. Genes are clustered by program (as in Figure 2B; codes are shown above and below). [Figure 2D]Bipartite graph showing the relationship between six co-functional modules (left) and eleven co-regulated programs (right). Arrows: module genes activate the program (i.e., KO inhibits the program); T-head arrows: module genes inhibit the program (i.e., activate the program) (arrows are determined by significant mean differences). Significant genes are labeled. [Figure 3A] Figure 2B shows the E3 gene regulatory network. The model shown in Figure 2C, based on perturbations (KO) in an E3 ligase, shows the regulatory relationships to other E3 ligases whose expression is affected. Arrows: Perturbed E3 activates expression of the target (i.e., KO inhibits expression). Crossed arrows: Perturbed E3 inhibits expression of the target (i.e., KO activates expression). The three E3 ligases are highly regulated "authorities" in the E3 network. [Figure 3B] UMAP embeddings of single cell profiles shaded by Gaussian kernel density estimates of cells using control (top left), M1 (top right) or M5 (bottom) guides. [Figure 3C-E] Figure 3C shows supervised UMAP embeddings of DC2.1, DC2.2, and DC2.3 cell profiles, using the cells' cofunctional module assignment as the response level, shaded by their guide's module assignment (shading code). Figure 3D shows the average Wasserstein distance (bars) between cells with guides from different cofunctional modules (rows, columns). Figure 3E shows the odds ratios (bars) for significant enrichment (^) or depletion (v) of DC subsets (rows) in cells with guides from each cofunctional module (columns) (FDR<0.15, one-tailed Fisher's exact test). [Figure 3F-G]Figure 3F is a graph showing the physical interactions (gray; experimental score >0, STRING database (DB)) or no physical interactions (white) between each pair of 78 E3 ligases and adaptors with at least 24 interactions (with any of 165 E3 ligases out of 329 regulators). The full matrix is ​​shown in Figure 11G. Shading indicates 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. Bars: co-functional modules. Rows and columns are hierarchically clustered. Figure 3G is a chart showing the estimated activity scores (bars) of 32 TFs (columns) whose target genes are significantly (FDR < 0.1) induced or repressed when perturbing each of the 41 E3s and associated genes (rows). The full matrix is ​​shown in Figure 11J. [Figure 3H] A set of Venn diagrams showing intersections between TF targets (Discriminant Regulon Expression Analysis (DoRothEA)), E3 expression targets, and gene programs. [Figure 3I] A set of Venn diagrams showing intersections between TF targets (DoRothEA), E3 expression targets, and gene programs. [Figure 4A] A pair of heatmaps showing the association of E3 regulators with independent factors from independent component analysis (ICA). The coefficient of determination (CR) for the effect of each of the 203 perturbed genes on 1,041 genes (left matrix columns, sum of CR > 25%) or components of the CUL4-RBX1-DET1-RFWD2 complex (right matrix columns) is shown by each of the 15 latent factors (rows, main panel) and across all 15 factors (bottom). [Figure 4B-D]Figure 4B is a chart showing effect sizes (positive or negative; bars) for significantly affected genes (columns; outlier readings, separated by the direction of effect) upon perturbation of each regulator gene associated with the indicated factor (rows; outliers based on their weight in the confusion matrix). Left bar: co-functional modules; top bar: gene programs from the regulatory model. Figure 4C is a UMAP embedding of the cell profile (Figure 1C) shaded by the expression score of factor 5.1. Figure 4D is a UMAP embedding of the cell profile (Figure 1C) shaded by the expression score of factor 5.2. [Figure 4E-G] Figure 4E is a chart showing effect sizes (positive or negative; bars) for significantly affected genes (columns; outlier readings, separated by the direction of effect) upon perturbation of each regulator gene associated with the indicated factor (rows; outliers based on their weight in the confusion matrix). Left bar: co-functional modules; top bar: gene programs from the regulatory model. Figure 4F is a UMAP embedding of the cell profile (Figure 1C) shaded by the expression score of factor 6.1. Figure 4G is a UMAP embedding of the cell profile (Figure 1C) shaded by the expression score of factor 6.2. [Figure 4H-J] Figure 4H is a graph showing effect sizes (positive or negative; bars) for significantly affected genes (columns; outlier readings, separated by the direction of effect) upon perturbation of each regulator gene associated with the indicated factor (rows; outliers based on their weight in the confusion matrix). Left bar: co-functional modules; top bar: gene programs from the regulatory model. Figure 4I is a UMAP embedding of the cell profile (Figure 1C) shaded by the expression score of factor 2.1. Figure 4J is a UMAP embedding of the cell profile (Figure 1C) shaded by the expression score of factor 2.2. [Figure 5A-B]Figure 5A is a bar graph showing the number of genes (y-axis) significantly affected, additively or non-additively, by combinatorial perturbations (x-axis) within modules (left bars) or between modules (right bars). Figure 5B is a set of scatterplots showing intra-module interactions within the depicted modules. The y-axis shows the fold change in expression observed in cells with perturbations to two genes from the same module (vs. control), while the x-axis shows the predicted fold change from an additive model based on two individual perturbations to each of 1,041 genes (dots). The slope of the first principal component (PC) (red line) and the variance of the observed double knockout (R2) explained by the single knockout are labeled. Module M4 is not shown due to insufficient numbers of double knockout cells. [Figure 5C] Heatmap showing significant effect sizes (bars; FDR<0.1) of perturbations at the level of individual modules (Mi), inter-module pairs (Mi:Mj; i≠j), and intra-module pairs (Mi:Mi) (rows) in each of 1,041 genes (columns; labeled by gene program). Bottom row: row-centered mean expression in control cells. [Figure 5D] This chart shows the dichotomized significant effect sizes (FDR<0.1) on gene expression due to single perturbations in regulators from M3 or M5 (rows; only genes with significant interaction terms), their additive effects (M3+M5), their interaction terms (M3:M5), and the observed combined effects (columns). [Figure 5E] FIG. 1 is a schematic diagram outlining the comβVAE method for predicting combinatorial perturbations. [Figure 5F] A set of boxplots showing the distribution of coefficients of determination (y-axis; R2 is 7 times using the same hyperparameters) of fold changes of 1,041 genes under different Kullback-Leibler (KL) loss weights (x-axis) for individual modules (Mi) and inter-module combinations (Mi:Mj; i ≠ j). [Figure 5G]This is a set of bar graphs showing the distribution of coefficients of determination (R², y-axis) for fold changes of 1,041 genes from seven runs using the same hyperparameters for the indicated inter-module combinations (labeled on top) when the model (beta = 6.0) was trained only on data from single KOs from all modules (M) or from single KOs from all modules and dual KOs from one or two pairs of modules (Mi:Mj; i ≠ j) (x-axis). Boxes indicate the first (Q1), second (Q2, median), and third (Q3) quartiles, and the bottom and top legs indicate the intervals [Q1 - 1.5 IQR, Q1] and [Q3, Q3 + 0.5 IQR], respectively. [Figure 6A-B] Figure 6A is a heatmap showing significant MAGMA Z-scores (bars; trait-specific; Bonferroni α<0.1) for immune disease traits (columns) for modular M6E3 family genes (rows) with at least one significant score. Figure 6B is a set of heatmaps showing the significance (-log10 p-value, dot shading) and effect size (dot size) of heritability enrichment for each gene program (rows) for different immune traits (columns) associated with risk of inherited human immune disease by sc-linker analysis using single nucleotide polymorphism (SNP) annotation combined with the intersection of Roadmap and ABC gene enhancer binding strategies (left) or by MAGMA (right). [Figure 6C-D] Figure 6C is a heat map showing gene programs expressed in immune and non-immune cells during immune disease progression. Shown are enrichment (bars) of gene programs (columns) for cell-type-specific disease progression programs (rows) in humans for various cell types and diseases. Figure 6D is a heat map showing gene programs expressed in immune and non-immune cells during immune disease progression. Shown are enrichment (bars) of gene programs (columns) for cell-type-specific disease progression programs in DCs and macrophages in ulcerative colitis (UC), fibrosis, asthma, and COVID-19. [Figure 6E-F]Figure 6E is a heatmap showing the regulation coefficients (bars, from the model in Figure 2C) of the influence of perturbed regulators (rows) on the expression of genes (columns) with rare variants associated with inflammatory bowel disease (IBD) that also have at least one significantly highly regulated E3 family member. Figure 6F is a photograph showing the significance (-log10 (p-value), dot shading) and effect size (dot size) of heritability enrichment of gene programs (rows) for Crohn's disease (CD) or IBD based on rare variants (CD:SAIGE-GENE) or common variants (IBD:MAGMA and CD:MAGMA). [Figure 7] Figure 1. DC life cycle regulated by E3 ligases. ICA factors and their key regulators grouped into each DC life cycle stage are shown in boxes. Bottom: UMAP embedding of cell profiles (Figure 1C) shaded by expression scores (bars) of migration-related factors. [Figure 8A-D] Figure 8A is a graph showing forward scatter (x-axis) vs. side scatter (y-axis) of selected viable perturbed BMDCs. Figure 8B is a graph showing forward scatter (x-axis) vs. side scatter (y-axis) of selected single perturbed BMDCs. Figure 8C is a graph showing GFP fluorescence (x-axis; Cas9 mouse cells) vs. mKate2 fluorescence (y-axis; Perturb-Seq vector) in selected mKate2+GFP+ cells. Figure 8D is a graph showing the distribution of mKate2 expression (x-axis) in sorted viable single cells. [Figure 8E] FIG. 1 is a schematic diagram showing a detailed PerturbDecode workflow. [Figure 8F-H]Figure 8F is a graph showing the cumulative distribution function (CDF) (y-axis) of Pearson's r (x-axis) between effect sizes of guides targeting the same gene, different genes, one gene and one non-targeting control, or one gene and one intergenic control. Figure 8G 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 the non-targeting control, intergenic control, or targeting guide (combinations of guides targeting the same gene) (x-axis). ****P<2.2*10-16, one-sided Wilcoxon rank-sum test. Figure 8H is a graph showing significant effect sizes (bars; negative / positive fold change; FDR<0.1) of perturbations of each of the 544 targets (rows), which are also a subset of the 6,685 genes with tested expression and the other 544 targets (columns). Rows and columns are ordered alphabetically. 137 of the 539 genes had their own expression significantly negatively affected (diagonal line). [Figure 8I] Scatter plot showing the number of genes (y-axis) whose expression was significantly (FDR<0.1) affected by the perturbation of each of the 849 perturbed genes (out of 13,811 detected genes) and the mean expression of these perturbed genes (x-axis, normalized log1p). Pearson's r and significance are indicated in the upper left. [Figure 8J] A set of violin plots showing the distribution of the number of genes (y-axis) that were significantly affected (FDR<0.1) by genetic perturbation, either included ("expressed") or not ("non-expressed") among the 13,811 detected genes. ****p-value<10-4, one-sided Wilcoxon rank sum test. [Figure 9A] 1 is a chart showing the mean expression (dot shading, mean normalized log1p expression) and percentage of expressing cells (dot size) of differentially expressed genes (columns) in each of 10 cell clusters (rows). [Figure 9B-C]Figure 9B is a chart showing the mean expression (dot shading, mean normalized log1p expression) and percentage of expressing cells (dot size) of differentially expressed genes (columns) for DC2 marker genes (rows). Figure 9C is a chart showing the mean expression (dot shading, mean normalized log1p expression) and percentage of expressing cells (dot size) of differentially expressed genes (columns) for mDC marker genes (rows). [Figure 9D-E] Figure 9D is a chart showing the mean expression (dot shading, mean normalized log1p expression) and percentage of expressing cells (dot size) of differentially expressed genes (columns) for DC1 marker genes (rows). Figure 9E is a chart showing the mean expression (dot shading, mean normalized log1p expression) and percentage of expressing cells (dot size) of differentially expressed genes (columns) for pDC marker genes (rows). [Figure 9F-G] Figure 9F is a chart showing the mean expression (dot shading, mean normalized log1p expression) and percentage of expressing cells (dot size) of differentially expressed genes (columns) in M1 marker genes (rows). Figure 9G is a chart showing the mean expression (dot shading, mean normalized log1p expression) and percentage of expressing cells (dot size) of differentially expressed genes (columns) in M2 marker genes (rows). [Figure 9H-I] Figure 9H is a UMAP embedding of 519,535 cell profiles (Figure 1C) shaded by DC (DC1+DC2+mDC) gene signature score. Figure 9I is a UMAP embedding of 519,535 cell profiles (Figure 1C) shaded by macrophage signature score. [Figure 9J-K] Figure 9J is a UMAP embedding of 3,655 unperturbed, unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3 h) BMDC profiles shaded by treatment. Figure 9K is a UMAP embedding of 3,655 unperturbed, unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3 h) BMDC profiles shaded by estimated cell cycle phase. [Figure 9L-O] Figure 9L shows UMAP embeddings of 3,655 unperturbed, unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3-hour) BMDC profiles shaded by the signature scores of the top 100 unregulated genes in cluster 1 of Figure 1C. Figure 9M shows UMAP embeddings of 3,655 unperturbed, unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3-hour) BMDC profiles shaded by the signature scores of the top 100 unregulated genes in cluster 2 of Figure 1C. Figure 9K shows UMAP embeddings of 3,655 unperturbed, unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3-hour) BMDC profiles shaded by the signature scores of the top 100 unregulated genes in cluster 3 of Figure 1C. Figure 9O shows UMAP embeddings of 3,655 unperturbed unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3 h) BMDC profiles shaded by the signature scores of the top 100 unregulated genes in cluster 4 of Figure 1C. [Figure 9P-S]Figure 9P shows UMAP embeddings of 3,655 unperturbed, unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3-hour) BMDC profiles shaded by the signature scores of the top 100 unregulated genes in cluster 5 of Figure 1C. Figure 9Q shows UMAP embeddings of 3,655 unperturbed, unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3-hour) BMDC profiles shaded by the signature scores of the top 100 unregulated genes in cluster 6 of Figure 1C. Figure 9R shows UMAP embeddings of 3,655 unperturbed, unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3-hour) BMDC profiles shaded by the signature scores of the top 100 unregulated genes in cluster 7 of Figure 1C. Figure 9S shows UMAP embeddings of 3,655 unperturbed unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3 h) BMDC profiles shaded by the signature scores of the top 100 unregulated genes in cluster 8 of Figure 1C . [Figure 9T-U] Figure 9T shows UMAP embeddings of 3,655 unperturbed, unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3 h) BMDC profiles shaded by the signature scores of the top 100 unregulated genes in cluster 9 of Figure 1C. Figure 9U shows UMAP embeddings of 3,655 unperturbed, unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3 h) BMDC profiles shaded by the signature scores of the top 100 unregulated genes in cluster 10 of Figure 1C. [Figure 9V] UMAP embeddings of 3,655 unperturbed, unstimulated BMDC profiles and 4,027 unperturbed and LPS-stimulated (3 h) BMDC profiles shaded by predicted major cell subtypes. [Figure 9W]Bar graphs showing the percentage of cells (y-axis) of each of the four major subtypes (legend) in screening unperturbed unstimulated, unperturbed LPS-stimulated, and perturbed LPS-stimulated data (x-axis). *P<2.2*10-16, one-tailed Fisher's exact test. [Figure 9X] Heatmap showing odds ratios (bars) for enrichment or depletion (FDR<0.15, one-tailed Fisher's exact test) of cells (rows) with perturbed genes in the cell cycle phases of the major subtypes (columns) in Figure 1C. [Figure 9Y] Heatmap showing odds ratios (bars) for enrichment or depletion (FDR<0.15, one-tailed Fisher's exact test) of cells (rows) with perturbed genes in cell cycle phases of 10 cell clusters (columns) in Figure 1C. [Figures 10A-E] Figure 10A is a UMAP embedding of cell profiles (Figure 1C) shaded by the expression scores of GP1 program genes. Figure 10B is a UMAP embedding of cell profiles (Figure 1C) shaded by the expression scores of GP2 program genes. Figure 10C is a UMAP embedding of cell profiles (Figure 1C) shaded by the expression scores of GP3 program genes. Figure 10D is a UMAP embedding of cell profiles (Figure 1C) shaded by the expression scores of GP4 program genes. Figure 10E is a UMAP embedding of cell profiles (Figure 1C) shaded by the expression scores of GP5 program genes. [Figure 10F-J]Figure 10F is a UMAP embedding of the cell profile (Figure 1C) shaded by the expression score of the GP6 program genes. Figure 10G is a UMAP embedding of the cell profile (Figure 1C) shaded by the expression score of the GP7 program genes. Figure 10H is a UMAP embedding of the cell profile (Figure 1C) shaded by the expression score of the GP8 program genes. Figure 10I is a UMAP embedding of the cell profile (Figure 1C) shaded by the expression score of the GP9 program genes. Figure 10J is a UMAP embedding of the cell profile (Figure 1C) shaded by the expression score of the GP10 program genes. [Figure 10K-L] Figure 10K is a UMAP embedding of cell profiles (Figure 1C) shaded by the expression scores of GP11 program genes. Figure 10L is a pair of heatmaps showing the Jaccard index (left) and percent overlap (right) between each gene program (rows, "A") and programs in an earlier, small-scale Perturb-Seq screen of 24 TFs for LPS-stimulated BMDCs (Dixit et al., Cell, 167:1853-1866.e17, 2016) (left, column, "B") or DC subset signatures (Maier et al., Nature, 580:257-262, 2020) (right, column, "B"). [Figure 10M] A set of violin plots showing the distribution of program scores (GP1-11; y-axis) for DC1-, DC2-, mDC-, and macrophage-like cell subsets (x-axis). *P<0.05 1 vs. rest one-sided Wilcoxon rank sum test. [Figure 11A] Figure 1 shows a chart showing the binarized regulatory effect (blue: negative; red: positive) of perturbation of each of the 60 E3 ligases in the model that significantly affected the expression of at least one other of the 60 E3 ligases for all 60 E3 ligases. Module membership is labeled on the left and top. Negative effects of KO on its own RNA levels are not shown. [Figure 11B]Figure 1 shows a chart showing the binarized regulatory effect (negative or positive) of perturbation of each of the 60 E3 ligases in the model that significantly affected the expression of at least one other of the 60 E3 ligases for 15 E3 ligases that affected and were affected by other E3s. Module membership is labeled to the left and above. The negative effect of KO on its own RNA levels is shown. [Figure 11C] A set of UMAP embeddings of cell profiles (Fig. 1C) shaded by Gaussian kernel density estimates of cells with control guides (top left) or guides targeting genes in each module (labeled above). [Figure 11D-E] Figure 11D is a supervised UMAP embedding of DC2.1, DC2.2, and DC2.3 cell profiles using the cells' co-functional module assignment as the response level (Figure 3C), shaded by the difference between macrophage and DC signature Z-scores. Figure 11E is a stacked bar graph showing the percentage of cells (y-axis) with guides targeting genes within each module (x-axis) belonging to each of the cell clusters in Figure 1C. [Figure 11F] 1D is a stacked bar graph showing the percentage of each cell (y-axis) in the cell cluster (x-axis) from FIG. 1C that has guides targeting genes in each module. [Figure 11G-H] Figure 11G is a chart showing the physical interactions (gray; experimental score >0, STRING DB) or their absence (white) between each pair of 165 E3 ligases (rows, columns) among 329 regulators. Shading indicates 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. Genes are sorted by module membership (shading above and to the left). Figure 11H is a network diagram showing the physical interactions (edges; experimental score > 0 in STRING DB) between NFkB signaling pathway components included in the regulatory model (nodes), shaded by significant (P < 0.05) positive or negative correlation of their perturbation effects. [Figure 11I] Top: A pair of charts showing the physical interaction (gray; experimental score >0, STRING DB; G shading code) or its absence (white) between each perturbed CLR E3 ligase (rows) and their CLR complex members (columns) containing adaptor domain proteins. Columns are ordered by CLR physical complex / interaction (boxes and dashed lines). Bottom: Same as above, except all significant covariates are displayed regardless of evidence of interaction. [Figure 11J] Heatmap showing the estimated activity scores (r bars) of 109 TFs (columns) whose target genes were significantly (FDR<0.1) induced or repressed (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). [Figure 11K] A set of Venn diagrams showing intersections between TF targets (DoRothEA), E3 expression targets, and gene programs. [Figure 12A-1] 10 is a chart showing the control factors (rows) associated with each factor (column) by their outlier weights in a confusion matrix. [Figure 12A-2] 10 is a chart showing the control factors (rows) associated with each factor (column) by their outlier weights in a confusion matrix. [Figure 12A-3] 10 is a chart showing the control factors (rows) associated with each factor (column) by their outlier weights in a confusion matrix. [Figure 12B] 10 is a chart showing member genes (columns) associated with each factor (column) by their outlier loading in the sequence of source signal prediction values. [Figure 12C-D] Figure 12C shows the "gn" main criterion (y-axis) of the Ladle expectation in randomly sampled unseen perturbed responses for ICA decompositions with various numbers of components (x-axis). Figure 12D shows the coefficient of determination (R2, y-axis) after matrix reconstruction in estimated components in randomly sampled unseen perturbed responses for ICA decompositions with various numbers of components (x-axis). [Figure 12E] A set of boxplots showing the distribution of the coefficient of determination (y-axis) in randomly sampled unseen perturbed responses for ICA decompositions (x-axis) with various numbers of components. [Figure 12F] A set of UMAP embeddings of cell profiles (Fig. 1C) shaded by the expression score of each subfactor (labeled above). [Figure 12G] 10 is a heatmap showing the Jaccard index (bar) for each pair of factors (columns and rows) based on genes with outlier loadings in the matrix of source signal predictions. [Figure 12H] 10 is a heatmap showing the Jaccard index (bar) for each pair of factors (columns and rows) based on the control factors with outlier weights in the per-factor confusion matrix. [Figure 13A] Heatmap showing the number of cells (bars, numbers) in an E3 screen with pairs of guides targeting genes within the same or paired modules (rows, columns). [Figure 13B] A chart showing the number of significant interaction terms (FDR<0.1, y-axis) for expression of each gene (x-axis) from combinatorial perturbations of all intra- and inter-module interactions. [Figure 13C] Stacked bar graph showing the number of target genes (y-axis, out of 1,041 in the control model) that have a significant effect on expression due to a single perturbation in a gene within one module (Mi, x-axis) or have a significant interaction term due to perturbations in two genes from the same (Mi:Mi, x-axis) or different (Mi:Mj, i≠j, x-axis) modules. [Figure 13D-E]Figure 13D is a chart showing the dichotomized significant effects (FDR<0.1) (positive or negative) on the expression of genes (rows, only genes with significant interaction terms) by single perturbations in regulators from two different modules (Mi, Mj, i≠j), their additive effects (Mi+Mj), their interaction terms (Mi:Mj), and the observed effects (columns). Gene program membership is labeled on the left. Figure 13E is a chart showing the dichotomized significant effects (FDR<0.1) (positive or negative) on the expression of genes (rows, only genes with significant interaction terms) by single perturbations in regulators from two different modules (Mi, Mj, i≠j), their additive effects (Mi+Mj), their interaction terms (Mi:Mj), and the observed effects (columns). Gene program membership is labeled on the left. [Figure 13F] A set of scatter plots showing the fold change in gene expression (x-axis) observed after inter-module combinatorial perturbations or predicted by the additive model for each of the 1,041 genes (points). R2: coefficient of determination for the observed fold change; MAE: mean absolute error of prediction. [Figure 13G-H] Figure 13G is a set of scatter plots showing the fold change in gene expression (y-axis) observed after inter-module combinatorial perturbations or predicted by the additive model for each of 1,041 genes with significant (FDR<0.1) inter-module interaction terms (x-axis). R2: Coefficient of determination for observed fold changes. Figure 13H is a set of scatter plots showing the fold change in gene expression (y-axis) observed after inter-module combinatorial perturbations or predicted by the additive model for each of 1,041 genes (points) with non-significant (FDR>=0.1) inter-module interaction terms (x-axis). R2: Coefficient of determination for observed fold changes. [Figure 14A]A set of scatter plots showing the fold change in gene expression (y-axis) observed after inter-module combinatorial perturbations or predicted by the comβVAE (x-axis) for each of the 1,041 genes (dots) or only for genes with significant (B, FDR<0.1) inter-module interaction terms. Diagonal entries reflect predictions in single knockouts. [Figure 14B] A set of boxplots showing the fold change in gene expression (y-axis) observed after inter-module combinatorial perturbations or predicted by the comβVAE (x-axis) for each of 1,041 genes with significant (FDR < 0.1) inter-module interaction terms. All boxes in the boxplots represent the first (Q1), second (Q2, median), and third (Q3) quartiles, and the bottom and top legs represent the intervals [Q1 - 1.5 IQR, Q1] and [Q3, Q3 + 1.5 IQR], respectively. [Figure 14C] A set of scatter plots showing the distribution of the coefficient of determination (top, y-axis, R2) and mean absolute error (bottom, y-axis, MAE) of the predictions of the comβVAE model for each module (Mi) or inter-module combination (Mi:Mj, i≠j) (x-axis) using the same hyperparameters seven times. [Figure 14D] A set of boxplots showing the distribution of coefficients of determination of fold changes (D, y-axis) of the comβVAE model for different KL loss weight values ​​(x-axis) for each module (Mi) or inter-module combination (Mi:Mj, i≠j) seven times using the same hyperparameters. [Figure 14E] A set of boxplots showing the distribution of coefficients of determination (y-axis, R2) for the indicated inter-module combinations (labeled above the panels) when the model (beta = 6.0) was trained seven times with the same hyperparameters using only data from cells perturbed once from all modules (M) or data from cells perturbed once from all modules and cells perturbed twice from one or two pairs of modules (Mi:Mj; i ≠ j) (x-axis). [Figure 14F]A set of boxplots showing the coefficient of determination (y-axis) of fold change in each module pair (panel) when the comβVAE model was trained with different KL loss weight values ​​(x-axis) and on singly perturbed cells only (red) or on both singly and twice perturbed cells of a particular module pair (green: M3M5; blue: M5M6; purple: M3M5 and M5M6). [Figure 14G] A set of boxplots showing the coefficient of determination (y-axis) of fold changes in select module pairs with relatively large numbers of genes with significant inter-module interaction terms (column headers) when the comβVAE was trained with different KL loss weight values ​​(x-axis) and trained on singly perturbed cells only or on both singly and doubly perturbed cells of a particular module pair (row labels). DETAILED DESCRIPTION OF THE INVENTION

[0155] I. Definition Unless otherwise defined, all technical terms, notations, and other scientific terms used herein are intended to have the meaning commonly understood by one of ordinary skill in the art to which the present invention pertains. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from what is commonly understood in the art.

[0156] The term "about" as used herein refers to a normal error range for the respective value, which would be readily understood by one of ordinary skill in the art. A reference to "about" with respect to a value or parameter herein includes (and describes) aspects directed to the value or parameter itself.

[0157] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, "an isolated peptide" means one or more isolated peptides.

[0158] Throughout this specification and the claims, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer or group of integers, but not the exclusion of any other integer or group of integers.

[0159] The terms "patient," "subject," or "individual," used interchangeably herein, refer to a human patient.

[0160] An "effective amount" refers to an amount of an agent (e.g., a therapeutic agent) effective to provide therapeutic / prophylactic benefits (e.g., as described herein) that outweigh any unwanted / undesirable side effects.

[0161] The term "pharmaceutical formulation" refers to a preparation in which the biological activity of one or more active ingredients is in a form such that it is effective and does not contain additional ingredients that are unacceptably toxic to the subject to whom the formulation is 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.

[0162] A "native sequence" protein, as used herein, refers to a protein comprising the amino acid sequence of a protein found in nature, including variants of a naturally occurring protein. As used herein, the term includes a protein isolated from its natural source or a protein that is recombinantly produced.

[0163] Unless otherwise indicated, the term "protein," as used herein, refers to 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 encompasses "full-length," unprocessed proteins and all forms of proteins that result from processing within a cell. The term also encompasses naturally occurring variants of proteins, such as splice variants or allelic variants, including amino acid substitution or deletion variants. The term also encompasses isolated regions or domains of proteins, such as the extracellular domain (ECD).

[0164] An "isolated" protein or peptide is one that is separated from a component of its natural environment. In some embodiments, the protein or peptide is purified to greater than 95% or 99% purity, as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC).

[0165] An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. Isolated nucleic acid includes a nucleic acid molecule contained within cells that ordinarily contain the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0166] As used herein, a "modulator" is an agent that modulates (e.g., increases, decreases, activates, or inhibits) a given biological activity, such as the interaction between two proteins or a downstream activity resulting from the interaction (e.g., direct or indirect interaction). A modulator or candidate modulator can be, for example, a small molecule, an antibody (e.g., a bispecific or multispecific antibody), an antigen-binding fragment (e.g., bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, ScFab, VH domain, or VHH domain), a peptide, a mimetic, an antisense oligonucleotide, or an inhibitory nucleic acid (e.g., an antisense oligonucleotide (ASO) or small interfering RNA (siRNA)).

[0167] By "increase" or "activate" is meant the ability to cause an overall increase, e.g., of 20% or more, 50% or more, or 75%, 85%, 90%, or 95% or more. In some aspects, increase or activate can refer to a downstream activity of a protein-protein interaction.

[0168] "Reduce" or "inhibit" refers to the ability to cause an overall decrease, for example, of 20% or more, 50% or more, or 75%, 85%, 90%, or 95% or more. In some aspects, reduce or inhibit can refer to a downstream activity of a protein-protein interaction.

[0169] "Affinity" refers to the sum total of the strength of non-covalent interactions between a single binding site of a molecule (e.g., a receptor) and its binding partner (e.g., a ligand). As used herein, "binding affinity," unless otherwise indicated, refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., a receptor and a ligand). The affinity of a molecule X for its partner Y is typically measured by the dissociation constant (K D Affinity can be measured by common methods known in the art, including those described herein.

[0170] As used herein, "complex" or "complex-type" refers to an association of two or more molecules that interact with each other through bonds and / or forces (e.g., van der Waals, hydrophobic, hydrophilic) that are not peptide bonds. In one aspect, the complex is a heteromultimer. The term "protein complex" or "polypeptide complex" as used herein should be understood to include complexes having non-protein entities (e.g., including, but not limited to, chemical molecules such as toxins or detection agents) conjugated to proteins in the protein complex.

[0171] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transfected cells," "transformed cells," and "transformants," which include the primary transformed cell and its progeny, regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to the parent cell and may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein. In some aspects, host cells are stably transformed with exogenous nucleic acid. In other aspects, host cells are transiently transformed with exogenous nucleic acid.

[0172] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors as self-replicating nucleic acid structures and vectors that integrate into the genome of a host cell into which they are introduced. Some vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors."

[0173] The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (e.g., bis-Fab), so long as they exhibit the desired antigen-binding activity.

[0174] An "antigen-binding fragment" or "antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antigen-binding fragments include, but are not limited to, bis-Fab; Fv; Fab; Fab, Fab'-SH; F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv, ScFab); and multispecific antibodies formed from antibody fragments.

[0175] A "single domain antibody" refers to an antibody fragment that comprises all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In some aspects, a single domain antibody is a human single domain antibody (see, e.g., U.S. Pat. No. 6,248,516). Examples of single domain antibodies include, but are not limited to, VHHs.

[0176] A "Fab" fragment is an antigen-binding fragment produced by papain digestion of an antibody and consists of an entire light chain, the variable region domain (VH) of the heavy chain, and the first constant domain (CH1) of one heavy chain. Papain digestion of an antibody produces two identical Fab fragments. Pepsin treatment of an antibody produces a single large F(ab')2 fragment, which roughly corresponds to two disulfide-linked Fab fragments with bivalent antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is the designation used herein for Fab' in which one or more cysteine ​​residues in the constant domains bear a free thiol group. F(ab')2 antibody fragments were originally produced as a pair of Fab' fragments with hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0177] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification, or by recombinantly engineering a nucleic acid encoding the antibody heavy chain. Thus, an intact antibody composition can include antibody populations in which all Lys447 residues have been removed, antibody populations in which the Lys447 residue has not been removed, and antibody populations having a mixture of antibodies with and without the Lys447 residue.

[0178] An "Fv" consists of a tight, non-covalently associated dimer of one heavy- and one light-chain variable region domain. The folding of these two domains results in six hypervariable loops (three loops from each H and L chain) that contribute amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three antigen-specific CDRs) has the ability to recognize and bind antigen, although often with lower affinity than the entire binding site.

[0179] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein and refer to an antibody having a structure substantially similar to a native antibody structure or having a heavy chain that includes an Fc region as defined herein.

[0180] "Single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment comprising the VH and VL antibody domains connected in a single polypeptide chain. Preferably, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding. For reviews of scFvs, see Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994); Malmborg et al., J. Immunol. Methods 183:7-13, 1995.

[0181] The term "small molecule" refers to any molecule having a molecular weight of about 2000 daltons or less, e.g., about 1000 daltons or less. In some embodiments, a small molecule is a small organic molecule.

[0182] As used herein, the term "mimetic" or "molecular mimetic" refers to a polypeptide that has sufficient similarity (e.g., secondary structure, tertiary structure) in conformation and / or binding capacity to a given polypeptide or to a portion of that polypeptide to bind to a binding partner of that polypeptide. A mimetic may bind to a binding partner with equal, lesser, or greater affinity than the polypeptide it mimics. A molecular mimetic may or may not have appreciable amino acid sequence similarity to the polypeptide it mimics. A mimetic may be naturally occurring or engineered. In some embodiments, a mimetic is a mimetic of a member of a binding pair. In other embodiments, a mimetic is a mimetic of another protein that binds to a member of a binding pair. In some embodiments, a mimetic may perform all of the functions of the mimicked polypeptide. In other embodiments, a mimetic does not perform all of the functions of the mimicked polypeptide.

[0183] As used herein, the term "conditions that permit binding" of two or more proteins to one another refers to conditions (e.g., protein concentration, temperature, pH, salt concentration) under which two or more proteins would interact in the absence of a modulator or candidate modulator. Conditions that permit binding will vary for individual proteins and may differ between protein-protein interaction assays (e.g., surface plasmon resonance assays, biolayer interferometry assays, enzyme-linked immunosorbent assays (ELISAs), extracellular interaction assays, and cell surface interaction assays).

[0184] "Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, 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 algorithms necessary to achieve maximal alignment over the entire length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code, together with user documentation, has been filed with the U.S. Copyright Office, Washington, DC 20559, and is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California) or can be compiled from its 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 do not vary.

[0185] In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or in contrast to a given amino acid sequence B (alternatively, it can be written as a given amino acid sequence A having or containing a particular % amino acid sequence identity to, with, or in contrast to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y where X is the number of amino acid residues scored as perfect matches by the sequence alignment program ALIGN-2 in the program's alignment of A and B, and Y is the total number of amino acid residues in B. It will 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 of A to B will not be equal to the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values ​​used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0186] As used herein, "treatment" (and its grammatical variations, e.g., "treat" or "treating") refers to a clinical intervention in an attempt to alter the natural course of the individual being treated and can be performed prophylactically or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the onset or recurrence of disease (e.g., preventing a dendritic cell-associated disease or disorder and / or its inflammation or symptoms), reducing or preventing secondary infection in patients with an infectious disease (e.g., reducing or preventing secondary infection of nervous tissue, immune cells, lymphatic tissue, and / or pulmonary tissue), alleviating symptoms, diminishing any direct or indirect pathological consequences of the disease, slowing the rate of disease progression, ameliorating or alleviating the disease state, and remission or improved prognosis.

[0187] The "pathology" of a disease or condition includes all phenomena that impair the well-being of the patient.

[0188] "Amelioration," "ameliorating," "alleviating," "alleviating," or equivalents thereof refer to both therapeutic and prophylactic or preventative treatment, the purpose of which is to improve, prevent, slow down (lessen), reduce, or inhibit a disease or disorder, e.g., a disease or condition related to dendritic cells and / or inflammation. Those in need of treatment include those already with the disease or condition as well as those prone to have the disease or condition, or those in need of disease or condition prevention.

[0189] As used herein, the term "treatment" or "treating" refers to a clinical intervention designed to alter the natural course of the treated individual or cell during the course of clinical pathology. Desirable effects of treatment include delaying or slowing the rate of disease progression, ameliorating or alleviating the disease state, and achieving remission or improved prognosis. For example, an individual is "treated" successfully if one or more symptoms associated with cancer, an inflammatory disease, or an autoimmune disease are alleviated or eliminated. Indicators of successful cancer treatment include, but are not limited to, a reduction in the proliferation (or destruction) of cancerous cells, a decrease in symptoms resulting from the disease, an improvement in the quality of life of those suffering from the disease, a reduction in the dose of other medications required to treat the disease, a delay in disease progression, and / or an increase in the individual's survival. Treatment herein includes, among others, adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (e.g., locally advanced cancer therapy), and metastatic cancer therapy. Treatment can be first-line therapy (e.g., the patient may not have been previously treated or has not received prior systemic therapy) or second-line therapy or later.

[0190] As used herein, "in combination with" or "in combination with" refers to the administration of one therapeutic modality in addition to another therapeutic modality, e.g., a therapeutic regimen that includes the administration of a modulator or modified cell provided herein and one or more additional agents. Thus, "in combination with" refers to the administration of one therapeutic modality before, during, or after the administration of another therapeutic modality to a patient.

[0191] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Cancer includes solid 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, 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), urothelial carcinoma (UC), including 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), including extensive-stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), including locally advanced unresectable NSCLC (e.g., IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC), adenocarcinoma of the lung, or squamous cell carcinoma (e.g., squamous cell carcinoma (e.g., squamous cell carcinoma of the lung)); 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., gastroesophageal junction (GEJ) cancer) or gastrointestinal cancer and gastrointestinal stromal cancer; glioblastoma; urinary tract cancer; liver cancer; breast cancer (e.g., , HER2+ breast cancer and triple-negative breast cancer (TNBC (e.g., early stage TNBC (eTNBC)), estrogen receptor (ER-), progesterone receptor (PgR-), and HER2 (HER2-) negative); prostate cancer such as castration-resistant prostate cancer (CRPC), peritoneal cancer, hepatocellular carcinoma, gastric cancer or stomach cancer (including gastrointestinal cancer and gastrointestinal stromal cancer); pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)); glioblastoma; cervical cancer (e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and / or recurrent PD-L1 positive cervical cancer); ovarian cancer;liver cancer (e.g., hepatocellular carcinoma (HCC), e.g., locally advanced or metastatic HCC and / or unresectable HCC); liver cancer; colon cancer; rectal cancer; colorectal cancer (CRC; e.g., CRC with microsatellite stable (MSS) and microsatellite instability (MSI) low (MSI-Low)); intrauterine or uterine cancer; salivary gland carcinoma; prostate cancer; vulvar cancer; thyroid cancer; liver cancer; anal cancer; penile cancer; melanoma (including superficial metastatic melanoma, melanoma malignant melanoma, acral melanoma, and nodular melanoma); multiple myeloma and B-cell lymphoma (including low-grade / follicular non-Hodgkin's lymphoma (NHL)); small lymphocytic (SL) NHL; intermediate-grade / follicular NH L; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade non-cleaved small cell NHL; bulky mass disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myoblastic leukemia (AML); hairy cell leukemia; chronic myeloblastic leukemia (CML); post-transplant lymphoproliferative disorder (PTLD); and myelodysplastic syndromes (MDS), as well as abnormal blood vessel growth associated with phacomatosis, edema (such as that associated with brain tumors), Meigs syndrome, brain cancer, head and neck cancer, and related metastases.

[0192] A "disorder" or "disease" is any condition that may benefit from treatment, including, but not limited to, disorders associated with any degree of abnormal cell proliferation, e.g., cancer, and disorders associated with inflammation and / or dysregulated immune responses, e.g., inflammatory and autoimmune diseases, including, but 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.

[0193] II. Modulators of protein-protein interactions In some aspects, the disclosure features modulators of protein-protein interactions; methods for identifying such modulators; and methods of treating a disease (e.g., cancer, an inflammatory disease, or an autoimmune disease) comprising administering a modulator of a protein-protein interaction. In any of these aspects, the protein-protein interaction can be a direct interaction, e.g., an interaction in which interacting members physically contact each other (e.g., bind to each other). Alternatively, in some aspects, the protein-protein interaction can be an indirect interaction, e.g., an interaction in which interacting members do not physically contact each other. An indirect protein-protein interaction can be identified by determining a causal relationship between the expression, activity, and / or abundance of a first member of the protein-protein interaction and the expression, activity, and / or abundance of a second member of the protein-protein interaction (e.g., perturbation of a first member of the protein-protein interaction in a biological system (e.g., an organism, tissue, or cell) has a measurable effect on the second member of the protein-protein interaction (e.g., its expression, activity, and / or abundance). In some aspects, proteins having an indirect interaction are associated within a pathway or network.

[0194] In some embodiments, a modulator of a protein-protein interaction directly interacts with (e.g., binds to) one or both members of the protein-protein interaction, hi other embodiments, a modulator of a protein-protein interaction does not directly interact with either member of the protein-protein interaction.

[0195] In some aspects, the disclosure features an isolated modulator of an interaction between a first protein and a second protein, wherein the protein-protein interaction is a direct interaction and the modulator decreases binding of the first protein to the second protein compared to binding in the absence of the modulator.

[0196] In some aspects, the disclosure features an isolated modulator of an interaction between a first protein and a second protein, wherein the protein-protein interaction is a direct interaction and the modulator increases binding of the first protein to the second protein compared to binding in the absence of the modulator.

[0197] In some aspects, the disclosure features an isolated modulator of an interaction between a first protein and a second protein, wherein the protein-protein interaction is an indirect interaction and the modulator decreases a downstream activity of one or both members of the protein-protein interaction compared to the downstream activity in the absence of the modulator.

[0198] In some aspects, the disclosure features an isolated modulator of an interaction between a first protein and a second protein, wherein the protein-protein interaction is an indirect interaction and the modulator increases a downstream activity of one or both members of the protein-protein interaction compared to the downstream activity in the absence of the modulator.

[0199] In some embodiments, the modulator comprises a pharmaceutically acceptable carrier.

[0200] A. Modulators of the Interaction Between a First Protein and a Second Protein direct interaction In some aspects, the disclosure features a modulator of an interaction between a first protein and a second protein, wherein the protein-protein interaction is a direct interaction and the modulator reduces binding of the first protein to the second protein and / or binding of the second protein to the first protein.

[0201] In some embodiments, the modulator reduces binding of the first protein to the second protein and / or the second protein to the first protein by at least 50%. In some embodiments, the reduction in binding 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., binding is abolished) compared to binding in the absence of the modulator, e.g., the reduction is between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, or 95% and 100%. In some embodiments, the modulator reduces binding of the first protein to the second protein and / or the second protein to the first protein by at least 90 percent (e.g., 90% to 100%). In some embodiments, the reduction in binding is at least 50% (e.g., 50% to 55%, 55% to 65%, 65% to 75%, 75% to 85%, 85% to 95%, or 95% to 100%), as measured, for example, by surface plasmon resonance, biolayer interferometry, or enzyme-linked immunosorbent assay (ELISA).

[0202] In some aspects, the disclosure features a modulator of an interaction between a first protein and a second protein, wherein the protein-protein interaction is a direct interaction and the modulator increases binding of the first protein to the second protein and / or binding of the second protein to the first protein.

[0203] In some embodiments, the modulator increases binding of the first protein to the second protein and / or the second protein to the first protein by at least 50%. In some embodiments, the increase in binding 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%, relative to binding in the absence of the modulator, e.g., the increase is between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, or 95% and 100%. In some embodiments, the modulator increases binding of the first protein to the second protein and / or the second protein to the first protein by at least 90 percent (e.g., 90% to 100%). In some embodiments, the increase in binding is at least 50% (e.g., 50% to 55%, 55% to 65%, 65% to 75%, 75% to 85%, 85% to 95%, or 95% to 100%), as measured, for example, by surface plasmon resonance, biolayer interferometry, or enzyme-linked immunosorbent assay (ELISA).

[0204] indirect interaction In some aspects, the disclosure features a modulator of an interaction between a first protein and a second protein, wherein the protein-protein interaction is an indirect interaction and the modulator disrupts a causal relationship between the expression, activity, and / or abundance of a first member of the protein-protein interaction and the expression, activity, and / or abundance of a second member of the protein-protein interaction. For example, in some aspects, the first protein controls the expression of the second protein (e.g., by controlling transcription or translation) and the modulator interferes with the control of expression; the first protein controls the activity of the second protein (e.g., as a component of an upstream signaling pathway) and the modulator interferes with the control of activity; and / or the first protein controls the abundance of the second protein (e.g., by targeting the second protein for degradation, e.g., by acting as a ubiquitin ligase) and the modulator interferes with the control of abundance.

[0205] In some aspects, disruption of the causal relationship alters the downstream activity of one or both members of the protein-protein interaction compared to the downstream activity in the absence of the modulator (e.g., increases or decreases the amount, intensity, or duration of the downstream activity).

[0206] Direct and indirect interactions In some embodiments, a modulator increases a downstream activity of one or both members of a protein-protein interaction (e.g., increases the amount, intensity, or duration of the downstream activity) compared to the downstream activity in the absence of the modulator. Downstream activity can include any biological activity that occurs as a direct or indirect result of the expression and / or activity of a member of a protein-protein interaction, e.g., regulation of transcription, signal transduction, and catalysis. In some embodiments, downstream activity is increased by at least 40%. In some embodiments, the increase 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%, e.g., the increase is between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, or 95% and 100%.

[0207] In some embodiments, the modulator reduces downstream activity compared to downstream activity in the absence of the modulator. In some embodiments, downstream activity is reduced by at least 40%. In some embodiments, 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 detectable levels), e.g., the reduction is between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, or 95% and 100%.

[0208] B. Small molecules In some embodiments, the modulator or candidate modulator is a small molecule. A small molecule is a molecule other than a binding polypeptide or antibody as defined herein. Small binding molecules can be identified and chemically synthesized using known methodologies (see, e.g., WO 00 / 00823 and WO 00 / 39585). Small binding molecules are typically less than about 2000 daltons in size (e.g., less than about 2000, 1500, 750, 500, 250, or 200 daltons in size), and such small organic molecules capable of preferably specifically binding to the polypeptides described herein can be identified without undue experimentation using well-known techniques. In this regard, it should be noted that techniques for screening small molecule libraries for molecules capable of binding to polypeptide targets are well known in the art (see, e.g., WO 00 / 00823 and WO 00 / 39585). The conjugated small molecule can be, for example, an aldehyde, ketone, oxime, hydrazone, semicarbazone, carbazide, primary amine, secondary amine, tertiary amine, N-substituted hydrazine, hydrazide, alcohol, ether, thiol, thioether, disulfide, carboxylic acid, ester, amide, urea, carbamate, carbonate, ketal, thioketal, acetal, thioacetal, aryl halide, aryl sulfonate, alkyl halide, alkyl sulfonate, aromatic compound, heterocyclic compound, aniline, alkene, alkyne, diol, amino alcohol, oxazolidine, oxazoline, thiazolidine, thiazoline, enamine, sulfonamide, epoxide, aziridine, isocyanate, sulfonyl chloride, diazo compound, or acid chloride.

[0209] In some embodiments, in the presence of the small molecule, binding of the first protein to the second protein is reduced (e.g., reduced by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., reduced by 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%).

[0210] In some embodiments, in the presence of the small molecule, binding of the first protein to the second protein is increased (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% increased, e.g., by 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%, 95% to 100%, or more than 100% increased).

[0211] In some embodiments, in the presence of the small molecule, downstream activity of the first protein and / or second protein is decreased (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decreased, e.g., between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, or 95% and 100% decreased).

[0212] C. Antibodies and Antigen-Binding Fragments In some embodiments, the modulator or candidate modulator is an antibody or antigen-binding fragment thereof that binds to one or both members of the protein-protein interaction, hi some embodiments, the antigen-binding fragment is a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain.

[0213] In some aspects, the modulator is a multispecific antibody, e.g., a bispecific antibody. In some aspects, the modulator is a bispecific or multispecific antibody that binds to multiple epitopes on one or both members of a protein-protein interaction. In some aspects, the modulator is a bispecific or multispecific antibody that binds to both members of a protein-protein interaction.

[0214] In some embodiments, in the presence of the antibody or antigen-binding fragment, binding of a first member of the protein-protein interaction to a second member of the protein-protein interaction is reduced (e.g., reduced by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., reduced by 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%).

[0215] In some embodiments, in the presence of the antibody or antigen-binding fragment, binding of the first member to the second member is increased (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% increased, e.g., between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, 95% and 100%, or more than 100% increased).

[0216] In some embodiments, in the presence of the antibody or antigen-binding fragment, a downstream activity of one or both members of the protein-protein interaction is reduced (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction, e.g., between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, or 95% and 100% reduction).

[0217] In some embodiments, in the presence of the antibody or antigen-binding fragment, a downstream activity of one or both members of the protein-protein interaction is increased (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% increased, e.g., between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, 95% and 100%, or more than 100% increased).

[0218] D. Peptides In some aspects, the modulator or candidate modulator is a peptide that binds to one or both members of a protein-protein interaction. The peptide can be a naturally occurring peptide or an engineered peptide. The peptide can bind to a binding partner with an affinity equal to, less than, or greater than the full-length protein. In some aspects, the peptide performs all of the functions of the full-length protein. In other aspects, the peptide does not perform all of the functions of the full-length protein.

[0219] In some embodiments, in the presence of the peptide, binding of a first member of a protein-protein interaction to a second member of the protein-protein interaction is reduced (e.g., reduced by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., reduced by 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%).

[0220] In some embodiments, in the presence of the peptide, binding of the first member to the second member is increased (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% increase, e.g., by 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%, 95% to 100%, or more than 100% increase).

[0221] In some embodiments, in the presence of the peptide, downstream activity of one or both members of the protein-protein interaction is decreased (e.g., decreased by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., decreased by 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%).

[0222] In some embodiments, in the presence of the peptide, downstream activity of one or both members of the protein-protein interaction is increased (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 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%, 95% to 100%, or more than 100%).

[0223] E. Imitation In some embodiments, the modulator or candidate modulator is a mimetic, e.g., a molecular mimetic, that binds to one or both members of a protein-protein interaction. In some embodiments, the mimetic may perform all of the functions of the mimicked polypeptide. In other embodiments, the mimetic does not perform all of the functions of the mimicked polypeptide.

[0224] In some embodiments, in the presence of the mimetic, binding of a first member of the protein-protein interaction to a second member of the protein-protein interaction is reduced (e.g., reduced by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., reduced by 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%).

[0225] In some embodiments, in the presence of the mimetic, binding of the first member to the second member is increased (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 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%, 95% to 100%, or more than 100%).

[0226] In some embodiments, in the presence of the mimetic, downstream activity of one or both members of the protein-protein interaction is decreased (e.g., decreased by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., decreased by 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%).

[0227] In some embodiments, in the presence of the mimetic, downstream activity of one or both members of the protein-protein interaction is increased (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 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%, 95% to 100%, or more than 100%).

[0228] F.PROTAC In some embodiments, the modulator or candidate modulator is a proteolysis-directed chimeric molecule (PROTAC) that binds to one or both members of a protein-protein interaction. PROTACs are described, for example, in Sakamoto et al., Proc Natl Acad Sci USA, 98(15):8554, 8559, 2001.

[0229] In some embodiments, in the presence of a PROTAC, binding of a first member of a protein-protein interaction to a second member of the protein-protein interaction is reduced (e.g., reduced by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, e.g., reduced by between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, or 95% and 100%). In some embodiments, in the presence of the PROTAC, binding of the first member to the second member is increased (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% increased, e.g., between 5% and 15%, between 15% and 25%, between 25% and 35%, between 35% and 45%, between 45% and 55%, between 55% and 65%, between 65% and 75%, between 75% and 85%, between 85% and 95%, between 95% and 100%, or more than 100% increased).

[0230] In some embodiments, in the presence of a PROTAC, the downstream activity of one or both members of the protein-protein interaction is reduced (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction, e.g., between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, or 95% and 100% reduction).

[0231] In some embodiments, in the presence of a PROTAC, the downstream activity of one or both members of the protein-protein interaction is increased (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, e.g., by 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%, 95% to 100%, or more than 100%).

[0232] In some embodiments, in the presence of a PROTAC, the abundance of one or both members of a protein-protein interaction is reduced (e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction, e.g., between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, or 95% and 100% reduction).

[0233] G. Assays for Modulation of Protein-Protein Interactions In some embodiments, binding of a first member of a protein-protein interaction to a second member of the protein-protein interaction is assessed in an assay for protein-protein interaction in the presence or absence of a candidate modulator. Modulation of an interaction may be identified as an increase in protein-protein interaction in the presence of a modulator as compared to the protein-protein interaction in the absence of the modulator, e.g., a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 90%, 95%, 100%, or greater than 100% (e.g., 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%, 95% to 100%, or greater than 100%) increase in protein-protein interaction. Alternatively, modulation may be identified as a decrease in protein-protein interaction in the presence of a modulator compared to protein-protein interaction in the absence of the modulator, e.g., a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 90%, 95%, or 100% (e.g., 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%) decrease in protein-protein interaction. The protein-protein interaction assay can be, for example, an SPR assay, a biolayer interferometry (BLI) assay, an enzyme-linked immunosorbent assay (ELISA), an extracellular interaction assay, or a cell surface interaction assay.

[0234] Exemplary methods for identifying modulators of protein-protein interactions, as well as agents that can modulate such interactions, are described in WO 2020 / 205626, which is incorporated herein by reference.

[0235] H. Delivery method The compositions (e.g., PROTACs, small molecules, antibodies, antigen-binding fragments, peptides, mimetics, antisense oligonucleotides, or siRNAs) utilized in the methods described herein can be administered by any suitable method, including, for example, intravenously, intramuscularly, subcutaneously, intradermally, transcutaneously, intra-arterially, intraperitoneally, intralesionally, intracranially, intra-articularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subconjunctivally, intravesicularly, transmucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, orally, transdermally, intravitreally (e.g., by intravitreal injection), by eye drop, by inhalation, by injection, by implantation, by infusion, by continuous infusion, by direct local perfusion of target cells, by catheter, by perfusion, in a cream, or in a lipid composition. The compositions utilized in the methods described herein can also be administered systemically or locally. The method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated). In some aspects, the modulator of protein-protein interactions is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracerebroventricularly, or intranasally. Dosing can be by any suitable route, for example, injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is brief or chronic. Various dosing schedules are contemplated herein, including, but not limited to, a single dose or multiple doses over various time periods, a bolus dose, and pulse infusion.

[0236] The modulators of protein-protein interactions described herein (and any additional therapeutic agents) may be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to physicians. The modulator need not be, but is optionally, formulated and / or co-administered with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents will depend on the amount of modulator present in the formulation, the type of disorder or treatment, and the other factors discussed above. These will generally be used in the same dosages and by any route of administration as described herein, or at about 1 to 99% of the dosages described herein, or at any dosage and by any route empirically / clinically determined to be appropriate.

[0237] III. Methods for identifying modulators of protein-protein interactions In some aspects, the disclosure features methods for identifying modulators of an interaction between a first member and a second member of a protein-protein interaction, and methods for identifying modulators of a downstream activity of one or both members of a protein-protein interaction, the methods including: (a) providing a candidate modulator (e.g., a candidate modulator described in Section II herein); (b) contacting the first member of the protein-protein interaction with a second member of the protein-protein interaction in the presence or absence of the candidate modulator under conditions that allow binding of the members of the protein-protein interaction; and (c) measuring binding of the members of the protein-protein interaction.

[0238] In some embodiments, the candidate modulator is provided to cells (e.g., mammalian cells), to cell culture medium, to conditioned medium, and / or to purified forms of the first and second members of the protein-protein interaction. In some embodiments, the candidate modulator is provided at a concentration 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 embodiments, the candidate modulator is provided at a concentration between 0.1 nM and 10 μM. In some embodiments, the candidate modulator is provided in solution, e.g., in a soluble form.

[0239] In some embodiments, a candidate modulator is identified as a modulator if the increase in binding is at least 70%. In some embodiments, 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., the increase is between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, 95% and 100%, or more than 100%). In some embodiments, the increase in binding is at least 70%.

[0240] In some embodiments, a candidate modulator is identified as a modulator if there is a decrease in binding of at least 70%. In some embodiments, the decrease 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%, or 100% (e.g., the decrease in binding is between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, or 95% and 100%). In some embodiments, the decrease in binding is at least 70%.

[0241] The protein-protein interaction assay can be, for example, an SPR assay, a biolayer interferometry (BLI) assay, an enzyme-linked immunosorbent assay (ELISA), an extracellular interaction assay as described in WO 2020 / 205626, or a cell surface interaction assay as described in WO 2020 / 205626.

[0242] A. Assaying modulation of the interaction between Fbxw11 and Nfkb1 and / or Nfkb2 In some aspects, the disclosure features a method for identifying a modulator of the interaction between F-box and WD repeat domain-containing 11 (Fbxw11) and nuclear factor kappa B subunit 1 (Nfkb1) or nuclear factor kappa B subunit 2 (Nfkb2), the method comprising: (a) providing a candidate modulator (e.g., a candidate modulator described in Section II herein); (b) detecting the candidate modulator under conditions that allow binding of Fbxw11 to Nfkb1 or Nfkb2. (c) contacting Fbxw11 with Nfkb1 or Nfkb2 in the presence or absence of a candidate modulator; and (c) measuring the binding of Fbxw11 to Nfkb1 or Nfkb2, wherein an increase or decrease in binding in the presence of the candidate modulator compared 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.

[0243] In some aspects, the disclosure features a method for identifying a modulator of downstream activity of Fbxw11, the method including: (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 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 modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of Fbxw11.

[0244] In some aspects, the disclosure features a method for identifying a modulator of downstream activity of Nfkb1 or Nfkb2, the method including: (a) providing a candidate modulator; (b) contacting Nfkb1 or Nfkb2 with Fbxw11 in the presence or absence of the candidate modulator 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 downstream activity in the presence of the candidate modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of Nfkb1 or Nfkb2.

[0245] In some embodiments, the increase or decrease in binding is at least 50% (e.g., 50% to 55%, 55% to 65%, 65% to 75%, 75% to 85%, 85% to 95%, or 95% to 100%) as measured by surface plasmon resonance, biolayer interferometry, or enzyme-linked immunosorbent assay (ELISA).

[0246] In some embodiments, the modulator is an inhibitor of Fbxw11 or downstream activity of Nfkb1 or Nfkb2.

[0247] In some aspects, the modulator is a modulator described in Section II herein, e.g., a proteolysis-directed chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain), a peptide, a mimetic, or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0248] In some embodiments where the modulator is an antibody or antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof binds to Fbxw11. In some embodiments, the antibody or antigen-binding fragment thereof binds to Nfkb1 and / or Nfkb2. For example, in some embodiments, the modulator is an antibody or antigen-binding fragment thereof that binds to Fbxw11, an antibody or antigen-binding fragment thereof that binds to Nfkb1 or Nfkb2, or an antibody or antigen-binding fragment thereof that binds to Fbxw11 and Nfkb1 and / or Nfkb2.

[0249] In some aspects, the change in downstream activity is a decrease in the amount, intensity, or duration of the downstream activity.

[0250] In some embodiments, the downstream activity of Fbxw11 is processing of Nfkb1 to generate active p50 and / or processing of Nfkb2 to generate active p52. In some embodiments, processing of Nfkb1 to generate active p50 and / or processing of Nfkb2 to generate active p52 is decreased in the presence of a modulator. The decrease 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., a 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% decrease). In other aspects, processing of Nfkb1 to produce active p50 and / or processing of Nfkb2 to produce active p52 is increased in the presence of a modulator. 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., 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%, 95% to 100%, or more than 100% increase).

[0251] In some embodiments, the downstream activity of Fbxw11, Nfkb1, and / or Nfkb2 is activation of an immune response. In some embodiments, activation of an immune response is decreased in the presence of a modulator. The decrease 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 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% decrease). In other embodiments, activation of an immune response 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% increase (e.g., 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%, 95% to 100%, or more than 100% increase).

[0252] B. Therapeutic Methods Using Modulators of the Interaction Between Fbxw11 and Nfkb1 and / or Nfkb2 In some aspects, the disclosure features a method for preventing or treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method comprising administering to the individual an effective amount of a modulator identified by the methods provided in Section III(A) above, thereby treating the individual.

[0253] In some aspects, the disclosure features a method for treating cancer in an individual, the method including 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. In some aspects, the disclosure features a method for treating an inflammatory or autoimmune disease in an individual, the method including 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.

[0254] C. Assay of modulation of the interaction between Rfwd2 and Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, or Wdr5 In some aspects, the present disclosure provides a method for detecting interactions between a Ring finger and WD repeat domain 2 (Rfwd2) and a query protein selected from forkhead box L2 (Foxl2), JunD, WD repeat domain 2 (Wdr82); E1A-binding protein p300 (Ep300); anaphase-promoting complex subunit 13 (Anapc13); Cullin 2 (Cul2); Cullin 5 (Cul5); HECT, UBA, and WWE domain-containing E3 ubiquitin protein ligase 1 (Huwe1); CREB-binding protein (Crebbp); S-phase kinase-associated protein 1 (Skp1a); neural precursor cell expressed, developmentally downregulated gene 8 (Nedd8); Cullin 1 (Cul1); and WD repeat domain 5 (Wdr5). The present invention features a method for identifying a modulator of an interaction between Rfwd2 and the query protein, the method comprising: (a) providing a candidate modulator (e.g., a candidate modulator described in Section II herein); (b) contacting Rfwd2 with the query protein in the presence or absence of the candidate modulator under conditions that allow binding of Rfwd2 to the query protein; and (c) measuring binding of Rfwd2 to the query protein, wherein an increase or decrease in binding in the presence of the candidate modulator compared to binding in the absence of the candidate modulator identifies the candidate modulator as a modulator of the interaction between Rfwd2 and the query protein.

[0255] In some aspects, the disclosure features a method of identifying a modulator of a downstream activity of Rfwd2, the method including: (a) providing a candidate modulator; and (b) detecting Rfwd2 in the presence or absence of the candidate modulator under conditions that allow binding of a query protein selected from Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5 to the query protein. 2, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5; and (c) measuring the downstream activity of Rfwd2, wherein a change in the downstream activity in the presence of the candidate modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of Rfwd2.

[0256] In some aspects, the disclosure features a method for identifying a modulator of a downstream activity of a query protein selected from Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5, the method including: (a) providing a candidate modulator; (b) contacting the query protein with Rfwd2 in the presence or absence of the candidate modulator under conditions that allow binding of the query protein 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 modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of the query protein.

[0257] In some embodiments, the increase or decrease in binding is at least 50% (e.g., 50% to 55%, 55% to 65%, 65% to 75%, 75% to 85%, 85% to 95%, or 95% to 100%) as measured by surface plasmon resonance, biolayer interferometry, or enzyme-linked immunosorbent assay (ELISA).

[0258] In some embodiments, the modulator is an inhibitor of a downstream activity of Rfwd2 or the query protein.

[0259] In some embodiments, the modulator is a modulator described in Section II herein, such as a proteolysis-directed chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain), a peptide, a mimetic, or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0260] In some embodiments where the modulator is an antibody or antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof binds to Rfwd2. In some embodiments, the antibody or antigen-binding fragment thereof binds to a query protein. For example, in some embodiments, the modulator is an antibody or antigen-binding fragment thereof that binds to Rfwd2, an antibody or antigen-binding fragment thereof that binds to a query protein, or an antibody or antigen-binding fragment thereof that binds to Rfwd2 and a query protein.

[0261] In some aspects, the change in downstream activity is a decrease in the amount, intensity, or duration of the downstream activity.

[0262] In some aspects, a downstream activity of Fbxw11, Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and / or Wdr5 is dendritic cell and / or macrophage migration, hi some aspects, dendritic cell and / or macrophage migration is decreased in the presence of the modulator. 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 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% reduction). In other aspects, 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% increase (e.g., 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%, 95% to 100%, or more than 100% increase).

[0263] D. Therapeutic Methods Using Modulators of the Interaction Between Rfwd2 and Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, or Wdr5 In some aspects, the disclosure features a method for preventing or treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method comprising administering to the individual an effective amount of a modulator identified by the methods provided in Section III(C) above, thereby treating the individual.

[0264] In some aspects, the disclosure features a method for treating an inflammatory or autoimmune disease in an individual, the method including 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.

[0265] In some aspects, the disclosure features a method for treating cancer in an individual, the method including 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.

[0266] E. Assaying the regulation of the interaction between a protein complex containing Ptpn11 and Rfwd2 and Cebp family transcription factors In some aspects, the disclosure features a method for identifying a modulator of an interaction between a protein complex comprising tyrosine-protein phosphatase non-receptor type 11 (Ptpn11) and a Ring finger and WD repeat domain 2 (Rfwd2) and a CCAAT enhancer-binding protein (Cebp) family transcription factor, the method including: (a) providing a candidate modulator (e.g., a candidate modulator described in Section II herein); (b) contacting the protein complex with the Cebp family transcription factor in the presence or absence of the candidate modulator under conditions that allow binding of the protein complex to the Cebp family transcription factor; and (c) measuring binding of the protein complex to the Cebp family transcription factor, wherein an increase or decrease in binding in the presence of the candidate modulator compared to binding in the absence of the candidate modulator identifies the candidate modulator as a modulator of the interaction between the protein complex and the Cebp family transcription factor.

[0267] In some aspects, the disclosure features a method for identifying a modulator of a downstream activity of a protein complex comprising Ptpn11 and Rfwd2, the method including: (a) providing a candidate modulator; (b) contacting the protein complex with a Cebp family transcription factor in the presence or absence of the candidate modulator under conditions that allow binding of v 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 modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of the protein complex.

[0268] In some aspects, the disclosure features a method for identifying a modulator of a Cebp family transcription factor, the method including: (a) providing a candidate modulator; (b) contacting the Cebp family transcription factor with a protein complex comprising Ptpn11 and Rfwd2 in the presence or absence of the candidate modulator under conditions that allow binding of the Cebp family transcription factor to the protein complex; and (c) measuring a downstream activity of the query protein, wherein a change in the downstream activity in the presence of the candidate modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of the query protein.

[0269] In some embodiments, the increase or decrease in binding is at least 50% (e.g., 50% to 55%, 55% to 65%, 65% to 75%, 75% to 85%, 85% to 95%, or 95% to 100%) as measured by surface plasmon resonance, biolayer interferometry, or enzyme-linked immunosorbent assay (ELISA).

[0270] In some embodiments, the modulator is an inhibitor of downstream activity of a Cebp family transcription factor and / or a protein complex comprising aPtpn11 and Rfwd2.

[0271] In some aspects, the modulator is a modulator described in Section II herein, e.g., a proteolysis-directed chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain), a peptide, a mimetic, or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0272] In some embodiments where the modulator is an antibody or antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof binds to one or both of Ptpn11 and Rfwd2. In some embodiments, the antibody or antigen-binding fragment thereof binds to a Cebp family transcription factor. For example, in some embodiments, the modulator is an antibody or antigen-binding fragment thereof that binds to Fbxw11, an antibody or antigen-binding fragment thereof that binds to one, two, or all three of Ptpn11, Rfwd2, and a Cebp family transcription factor, or an antibody or antigen-binding fragment thereof that binds to a Cebp family transcription factor and one or both of Ptpn11 and Rfwd2.

[0273] IV. METHODS OF PREVENTING OR TREATING APC-ASSOCIATED DISEASES OR DISORDERS In some aspects, the disclosure features a method for preventing or treating a disease or disorder associated with antigen presenting cells (APCs) and / or inflammation in an individual, the method comprising administering to the individual an effective amount of a modulator of a gene in Table 1 or Table 2, thereby treating the individual. Accordingly, in some aspects, the disclosure features a method for preventing or treating a disease or disorder associated with APCs and / or inflammation in an individual, the method comprising administering to the individual an effective amount of a modulator of a gene in Table 1, thereby treating the individual. In some aspects, the disclosure features a method for preventing or treating a disease or disorder associated with APCs and / or inflammation, the method comprising administering to the individual an effective amount of a modulator of a gene in Table 2, thereby treating the individual.

[0274] TIFF2026505163000001.tif247170TIFF2026505163000002.tif253170TIFF2026505163000003.tif40170

[0275] TIFF2026505163000004.tif249170TIFF2026505163000005.tif253170TIFF2026505163000006.tif99170

[0276] In some embodiments, the modulator modulates the expression of a gene of Table 1 or Table 2. In some embodiments, the modulator modulates the expression or activity of a protein encoded by a gene of Table 1 or Table 2.

[0277] In some embodiments, the modulator modulates the abundance of a protein encoded by a gene of Table 1 or Table 2, eg, modulates the degradation of the protein.

[0278] In some embodiments, a modulator alters the downstream activity of a protein encoded by a gene of Table 1 or Table 2 in the presence of the modulator compared to the downstream activity in the absence of the modulator.

[0279] In some embodiments, the modulator is an activator of downstream activity of a gene of Table 1 or Table 2. In some embodiments, the modulator increases downstream activity of a protein encoded by a gene of Table 1 or Table 2 (e.g., increases the amount, intensity, or duration of downstream activity) compared to the downstream activity in the absence of the modulator. Downstream activity can include any biological activity that occurs as a direct or indirect result of the expression and / or activity of a protein encoded by a gene of Table 1 or Table 2, e.g., transcriptional regulation, signal transduction, and catalysis. In some embodiments, downstream activity is increased by at least 40%. In some embodiments, the increase 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%, e.g., the increase is between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, or 95% and 100%.

[0280] In some embodiments, the modulator is an inhibitor of downstream activity of a gene of Table 1 or Table 2. In some embodiments, the modulator reduces downstream activity of a protein encoded by a gene of Table 1 or Table 2 compared to the downstream activity in the absence of the modulator. In some embodiments, downstream activity is reduced by at least 40%. In some embodiments, 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 detectable levels), e.g., the reduction is between 5% and 15%, 15% and 25%, 25% and 35%, 35% and 45%, 45% and 55%, 55% and 65%, 65% and 75%, 75% and 85%, 85% and 95%, or 95% and 100%.

[0281] In some aspects, the modulator is a modulator described in Section II herein, e.g., a proteolysis-directed chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain), a peptide, a mimetic, or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0282] In some embodiments where the modulator is an antibody or antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof binds to a protein encoded by a gene of Table 1 or Table 2.

[0283] In some embodiments, the disease or disorder associated with APCs and / or inflammation in the individual is a disease or disorder associated with dendritic cells (DCs), macrophages, glial cells, or B cells, e.g., the APCs are DCs, macrophages, glial cells (e.g., microglial cells, astrocytes, or oligodendrocytes), or B cells. In some embodiments, the APCs are DCs.

[0284] In some embodiments, the disease or disorder associated with APCs and / or inflammation is a neurodegenerative disease (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD)), arthritis, allergy, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or blastic plasmacytoma dendritic cell neoplasm. In some aspects, the disease or disorder associated with APCs and / or inflammation is selected from the group consisting of encephalitis, myelitis, meningitis, arachnoiditis, peripheral neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillaritis, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleuritis, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, sialadenitis / parotitis, cheilitis, pulpitis, mandibular inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, cecal inflammation, inflammation, appendicitis, proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendonitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis , cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, metritis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, presitis, balanoposthitis, chorioamnionitis, omphalitis, omphalitis, insulitis, hypophysitis, thyroiditis, parathyroiditis, adrenalitis, lymphangitis, or lymphadenitis.

[0285] In some embodiments, the gene in Table 1 or Table 2 is Vhl or Huwe1, and the modulator is a PROTAC that acts with Vhl as an E3 ligase, such as a PROTAC provided in Wang et al., Eur. J. Med. Chem., Jan 5;227:113906, 2022. In some embodiments, the gene in Table 1 or Table 2 is Huwe1, and the modulator is an agent provided in Crawford et al., Oncogene, 39(27):5001, 5014, 2020.

[0286] In some aspects, the disclosure features a method of monitoring the response of an individual having a disease or disorder associated with APCs and / or inflammation to treatment with a modulator of a gene of Table 1 or Table 2, the method comprising: (a) determining the expression level of the gene of Table 1 or Table 2 in a biological sample obtained from the individual at a time point after administration of the modulator; and (b) comparing the expression level of the gene of Table 1 or Table 2 in the biological sample to a reference level, thereby monitoring the response in the individual to treatment with the modulator.

[0287] In some aspects, the disclosure features a method of monitoring the response of an individual having a disease or disorder associated with APCs and / or inflammation to treatment with a modulator of a gene of Table 1, the method including: (a) determining the expression level of the gene of Table 1 in a biological sample obtained from the individual at a time point after administration of the modulator; and (b) comparing the expression level of the gene of Table 1 in the biological sample to a reference level, thereby monitoring the response in the individual to treatment with the modulator.

[0288] In some aspects, the disclosure features a method of monitoring the response of an individual having a disease or disorder associated with APCs and / or inflammation to treatment with a modulator of a gene in Table 2, the method including: (a) determining the expression level of the gene in Table 2 in a biological sample obtained from the individual at a time point after administration of the modulator; and (b) comparing the expression level of the gene in Table 2 in the biological sample to a reference level, thereby monitoring the response in the individual to treatment with the modulator.

[0289] In some embodiments, 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 administration of the modulator; (ii) the expression level of the gene in a reference population; (iii) a pre-assigned expression level for the gene; or (iv) the expression level of the gene in a biological sample obtained from the individual at an earlier time point after administration of the modulator.

[0290] In some embodiments, the expression level of a gene of Table 1 or Table 2 is decreased in a biological sample obtained from the individual compared to a reference level, and the method further comprises administering to the individual one or more additional doses of a modulator, wherein the modulator is an agent that increases expression and / or activity of a gene of Table 1 or Table 2.

[0291] In some embodiments, the expression level of a gene of Table 1 or Table 2 is increased in a biological sample obtained from the individual relative to a reference level, and the method further comprises administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that decreases expression and / or activity of a gene of Table 1 or Table 2.

[0292] V. Methods of Targeting CCR7 and Its Interacting Partners A. Treatment method In some aspects, the disclosure features a method for treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method including administering to the individual an effective amount of a modulator of the interaction between (a) one, two, or all three of LIM domain-binding protein 2 (Ldb2), Ring finger protein 165 (Rnf165), and TNF receptor-associated factor 2 (Traf2) and (b) chemokine receptor type 7 (CCR7).

[0293] In some aspects, the modulator is a modulator described in Section II herein, e.g., a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antibody-binding fragment thereof that binds to one, two, or all three of Ldb2, Rnf165, and Traf2 and / or that binds CCR7), a peptide, a mimetic, or an inhibitory nucleic acid (e.g., an ASO or siRNA). In some aspects, the modulator is a bispecific antibody comprising an antigen-binding domain that targets 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 that binds CCR7, and a second binding domain that targets the tumor microenvironment).

[0294] In some embodiments, the individual has cancer and the modulator is an agent that decreases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0295] In some embodiments, the individual has an inflammatory or autoimmune disease and the modulator is an agent that increases expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2. In other embodiments, the individual has cancer and the modulator is an agent that increases expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0296] In some embodiments, the inflammatory or autoimmune disease is a neurodegenerative disease (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD)), arthritis, allergy, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some embodiments, the inflammatory or autoimmune disease is Crohn's disease. In some embodiments, the inflammatory disease or autoimmune disease is selected from the group consisting of encephalitis, myelitis, meningitis, arachnoiditis, peripheral neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillaritis, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleuritis, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, sialadenitis / parotitis, cheilitis, pulpitis, mandibular inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, appendicitis, appendicitis, proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, medullary tract infections, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, presitis, balanoposthitis, chorioamnionitis, omphalitis, omphalitis, insulitis, hypophysitis, thyroiditis, parathyroiditis, adrenitis, lymphangitis, or lymphadenitis.

[0297] B. Methods for Increasing CCR7 Expression In some aspects, the disclosure features a method for increasing expression of CCR7 in an antigen-presenting cell (APC), the method including contacting the APC with an effective amount of an agent that decreases expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0298] An agent that decreases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2 can be, for example, a proteolysis-guiding chimeric molecule (PROTAC) (e.g., a PROTAC that directs the proteolysis of one, two, or all three of Ldb2, Rnf165, and Traf2); a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to one, two, or all three of Ldb2, Rnf165, and Traf2 and / or binds to CCR7); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA). In some embodiments, the agent is a bispecific antibody comprising an antigen-binding domain that targets 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 CCR7, and a second binding domain that targets the tumor microenvironment).

[0299] In some embodiments, 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% compared to expression in the absence of the agent (e.g., 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%, 95% to 100%, or more than 100% compared to expression in the absence of the agent). In some embodiments, CCR7 expression in APCs is increased by at least 10% compared to expression in the absence of the agent.

[0300] In some embodiments, the APC is a dendritic cell (DC), a macrophage, a glial cell (e.g., a microglial cell, an astrocyte, or an oligodendrocyte), or a B cell. In some embodiments, the APC is a DC.

[0301] In some embodiments, the APC is in an individual. In some embodiments, the individual has cancer.

[0302] C. Methods for Increasing APC Migration to Tumors and / or Lymph Nodes In some aspects, the disclosure features a method for increasing APC migration to a tumor and / or one or more lymph nodes in an individual (e.g., an individual having cancer), the method including administering to the individual an effective amount of an agent that decreases expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0303] An agent that decreases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2 can be, for example, a proteolysis-directing chimeric molecule (PROTAC) (e.g., a PROTAC that directs the proteolysis of one, two, or all three of Ldb2, Rnf165, and Traf2); a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to one, two, or all three of Ldb2, Rnf165, and Traf2 and / or binds to CCR7); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA). In some embodiments, the agent is a bispecific antibody comprising an antigen-binding domain that targets 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 CCR7, and a second binding domain that targets the tumor microenvironment).

[0304] In some embodiments, the individual has cancer, and APC migration 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% compared to migration in the absence of the agent (e.g., 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%, 95% to 100%, or more than 100%). In some embodiments, APC migration to the tumor site in the individual is increased by at least 10% compared to migration in the absence of the agent.

[0305] In some embodiments, APC migration to one or more lymph nodes 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% compared to migration in the absence of the agent (e.g., 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%, 95% to 100%, or more than 100%). In some embodiments, APC migration to one or more lymph nodes in an individual is increased by at least 10% compared to migration in the absence of the agent.

[0306] In some embodiments, the APC is a DC, a macrophage, a glial cell (e.g., a microglial cell, an astrocyte, or an oligodendrocyte), or a B cell. In some embodiments, the APC is a DC.

[0307] In some embodiments, the individual has cancer.

[0308] D. Methods for Increasing T Cell Homing to Tumors In some aspects, the disclosure features a method for increasing T cell homing to a tumor in an individual (e.g., an individual having cancer), the method including administering to the individual an effective amount of an agent that decreases expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2, where the agent increases dendritic cell migration to the tumor in the individual.

[0309] An agent that decreases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2 can be, for example, a proteolysis-guiding chimeric molecule (PROTAC) (e.g., a PROTAC that directs the proteolysis of one, two, or all three of Ldb2, Rnf165, and Traf2); a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to one, two, or all three of Ldb2, Rnf165, and Traf2 and / or binds to CCR7); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA). In some embodiments, the agent is a bispecific antibody comprising an antigen-binding domain that targets 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 CCR7, and a second binding domain that targets the tumor microenvironment).

[0310] In some embodiments, T cell homing to a 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% compared to T cell homing in the absence of the agent (e.g., 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%, 95% to 100%, or more than 100%). In some embodiments, T cell homing to a tumor in an individual is increased by at least 10% compared to T cell homing in the absence of the agent.

[0311] E. Combination Therapy Any of the methods in Sections V(A)-V(D) may further include administering to the individual or contacting the APC with one or more additional agents (e.g., administering the one or more additional agents before, during, or after treatment with a modulator of the interaction between (a) one, two, or all three of Ldb2, Rnf165, and Traf2 and (b) CCR7 or an agent that decreases expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2).

[0312] In some embodiments, the additional agent is an agent that modulates the expression of one or more members of module M3 as provided in Example 3, e.g., Akt1, Ankfy1, Apc, Arpc1b, Birc2, Bmil, 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 and an agent that regulates the expression of one or more of: 8, 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.

[0313] F. Cellular therapy by altering CCR7 or its interactors In some aspects, the disclosure features a method for treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method including administering to the individual an effective amount of a cell therapy (e.g., a cell therapy described in Section VIII herein) that includes a loss-of-function alteration in one, two, or all three of Ldb2, Rnf165, and Traf2.

[0314] In some aspects, the present disclosure provides genetically modified isolated cells that contain loss-of-function alterations in one, two, or all three of Ldb2, Rnf165, and Traf2.

[0315] In some aspects, the loss-of-function alteration is a loss-of-function mutation (e.g., a mutation that results in reduced or eliminated protein function, including a deletion). In some aspects, the loss-of-function alteration is a knockout (KO) mutation.

[0316] In some aspects, the disclosure features a method for treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method including administering to the individual an effective amount of a cell therapy comprising a gain-of-function alteration in CCR7.

[0317] In some aspects, the present disclosure provides genetically modified isolated cells comprising a gain-of-function alteration in CCR7.

[0318] In some aspects, the gain-of-function alteration is a gain-of-function mutation (e.g., a mutation that results in a decrease in gene function, including overexpression and gene duplication). In some aspects, the gain-of-function alteration is overexpression.

[0319] In some embodiments, the genetically modified isolated cell is a dendritic cell, a macrophage, a T cell, a TIL, or an NK cell.

[0320] In some aspects, the cell therapy is dendritic cell therapy, macrophage cell therapy, ACT, TIL therapy, engineered TCR therapy, CAR-T therapy, CAR-Treg therapy, or NK cell therapy.

[0321] G. Methods of Monitoring Response to Treatment In another aspect, the disclosure features a method for monitoring the response of an individual having 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 including: (i) determining the expression level of one or more of Ldb2, Rnf165, and Traf2 in a biological sample obtained from the individual at a time point after administration of the modulator; and (ii) comparing the expression level of one or more genes in the biological sample to a reference level, thereby monitoring the response in the individual to treatment with the modulator.

[0322] In some embodiments, 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 the individual prior to administration of the modulator; (ii) the expression level of one or more genes in a reference population; (iii) a pre-assigned expression level for one or more genes; or (iv) the expression level of one or more genes in a biological sample obtained from the individual at an earlier time point after administration of the modulator.

[0323] In some aspects, the individual has cancer and the expression level of one or more genes is increased in a biological sample obtained from the individual compared to a reference level, and the method further comprises administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that decreases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0324] In some aspects, the individual has an inflammatory or autoimmune disease, and the expression level of one or more genes is decreased in a biological sample obtained from the individual compared to a reference level, and the method further comprises administering one or more additional doses of a modulator to the individual; the modulator is an agent that increases the expression and / or activity of one, two, or all three of Ldb2, Rnf165, and Traf2.

[0325] VI. Methods for controlling migratory dendritic cells A. Methods of Treating Cancer, Inflammatory Disease, or Autoimmune Disease In some aspects, the disclosure features a method for treating cancer, an inflammatory disease, an autoimmune disease, or an infectious disease (e.g., an infectious disease that may benefit from an enhanced immune response) in an individual, the method including administering to the individual an effective amount of: (a) an agent that decreases the expression and / or activity of CCAAT / enhancer-binding protein beta (Cebpb); (b) an agent that decreases 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-inducer-obliterator 1 (Dido1).

[0326] An agent that decreases the expression and / or activity of Cebpb, decreases the expression and / or activity of Traf2, or increases the expression and / or activity of Dido1 can be, for example, a proteolysis-guided chimeric molecule (PROTAC); a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to Cebpb, Traf2; and / or Dido1); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0327] In another aspect, the disclosure features a method for treating an inflammatory disease, an autoimmune disease, or an infectious disease (e.g., an infectious disease caused by an excessive immune response) in an individual, the method including 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.

[0328] An agent that increases the expression and / or activity of Cebpb, increases the expression and / or activity of Traf2, or decreases the expression and / or activity of Dido1 can be, for example, a PROTAC; a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to Cebpb, Traf2, and / or Dido1); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0329] In some embodiments, the inflammatory or autoimmune disease is a neurodegenerative disease (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD)), arthritis, allergy, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some embodiments, the inflammatory or autoimmune disease is Crohn's disease. In some embodiments, the inflammatory disease or autoimmune disease is selected from the group consisting of encephalitis, myelitis, meningitis, arachnoiditis, peripheral neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillaritis, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleuritis, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, sialadenitis / parotitis, cheilitis, pulpitis, mandibular inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, appendicitis, appendicitis, proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, medullary tract infections, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, presitis, balanoposthitis, chorioamnionitis, omphalitis, omphalitis, insulitis, hypophysitis, thyroiditis, parathyroiditis, adrenitis, lymphangitis, or lymphadenitis.

[0330] In some embodiments, the autoimmune disease is associated with a decreased proportion of migratory dendritic cells (mDCs). In some embodiments, the individual has a loss-of-function mutation in Dido1.

[0331] B. Methods for increasing the proportion of MDC In another aspect, the disclosure features 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 including administering to the individual an effective amount of: (a) an agent that decreases the expression and / or activity of Cebpb; (b) an agent that decreases the expression and / or activity of Traf2; and / or (c) an agent that increases the expression and / or activity of death-inducer-obliterator 1 (Dido1).

[0332] An agent that decreases the expression and / or activity of Cebpb, decreases the expression and / or activity of Traf2, or increases the expression and / or activity of Dido1 can be, for example, a PROTAC; a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to Cebpb, Traf2, and / or Dido1); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0333] In some embodiments, the proportion of mDCs in an individual is the proportion in a tumor or tissue of the individual.

[0334] In some embodiments, the proportion of mDCs 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% compared to the proportion of mDCs in the individual in the absence of the agent (e.g., 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%, 95% to 100%, or more than 100% compared to the proportion of mDCs in the individual in the absence of the agent). In some embodiments, the proportion of mDCs in an individual (e.g., in the individual's tumor or tissue) is increased by at least 10% compared to the proportion in the absence of the agent.

[0335] C. Methods for Increasing Antitumor Immunity In another aspect, the disclosure features a method for increasing anti-tumor immunity in an individual (e.g., an individual having cancer), the method including administering to the individual an effective amount of: (a) an agent that decreases the expression and / or activity of Cebpb; (b) an agent that decreases the expression and / or activity of Traf2; and / or (c) an agent that increases the expression and / or activity of Dido1.

[0336] An agent that decreases the expression and / or activity of Cebpb, decreases the expression and / or activity of Traf2, or increases the expression and / or activity of Dido1 can be, for example, a PROTAC; a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to Cebpb, Traf2, and / or Dido1); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0337] In some embodiments, anti-tumor 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% compared to anti-tumor immunity in the individual in the absence of the agent (e.g., 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%, 95% to 100%, or more than 100% compared to anti-tumor immunity in the individual in the absence of the agent). In some embodiments, anti-tumor immunity in an individual (e.g., in the individual's tumor or tissue) is increased by at least 10% compared to anti-tumor immunity in the absence of the agent.

[0338] D. Methods for reducing the proportion of MDC In another aspect, the disclosure features a method for reducing the proportion of mDCs in an individual (e.g., an individual with an inflammatory disease or an autoimmune disease), the method including 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 increases the expression and / or activity of Dido1.

[0339] An agent that increases the expression and / or activity of Cebpb, increases the expression and / or activity of Traf2, or decreases the expression and / or activity of Dido1 can be, for example, a PROTAC; a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to Cebpb, Traf2, and / or Dido1); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0340] In some embodiments, the proportion of mDCs in an individual is the proportion in a tumor or tissue of the individual.

[0341] In some embodiments, the proportion of mDCs in an individual (e.g., in a tissue of an individual suffering from an inflammatory 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% compared to the proportion of mDCs in the individual in the absence of the agent (e.g., reduced by 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% compared to the proportion of mDCs in the individual in the absence of the agent). In some embodiments, the proportion of mDCs in an individual (e.g., in a tumor or tissue of the individual) is reduced by at least 10% compared to the proportion in the absence of the agent.

[0342] E. Methods for Reducing Autoimmune Activity (by Reducing the Proportion of mDCs) In another aspect, the disclosure features a method for reducing autoimmune activity in an individual (e.g., an individual having an autoimmune disease), the method including administering to the individual an effective amount of: (a) an agent that increases expression and / or activity of Cebpb; (b) an agent that increases expression and / or activity of Traf2; and / or (c) an agent that increases expression and / or activity of Dido1.

[0343] An agent that increases the expression and / or activity of Cebpb, increases the expression and / or activity of Traf2, or decreases the expression and / or activity of Dido1 can be, for example, a PROTAC; a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to Cebpb, Traf2, and / or Dido1); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0344] In some embodiments, autoimmune activity in an individual (e.g., in a tissue of an individual suffering from 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% compared to autoimmune activity in the individual in the absence of the agent (e.g., 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%, 95% to 100%, or 100% compared to autoimmune activity in the individual in the absence of the agent). In some embodiments, autoimmune activity in an individual (e.g., in a tumor or tissue of the individual) is reduced by at least 10% compared to autoimmune activity in the absence of the agent.

[0345] F. Combination Therapy Any of the methods in Sections VI(A)-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 decreases the expression and / or activity of Cebpb; an agent that decreases 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 decreases the expression and / or activity of Dido1).

[0346] In some embodiments, the additional agent is an agent that modulates the expression of one or more members of module M2 as presented in Example 3, such as Ago2, Ahr, Anapc13, Bach1, Baz1a, Bid, Bptf, Brca1, Brwd3, Btbd1, Cblc, Ccnf, Cdc27, Cntn4, Copa, Copb2, Coro1a, Cpn e9, Cul4b, Ddb1, E4f1, Ecel1, Fbxl14, Fbxl5, Fbxo11, Fbxo42, Fzr1, Gemin5, Gm10697, Gm9117, G tf2h2, 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, Pa2 g4, Pcif1, Ppp1r11, Prc1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah2, Taf3, Tdpoz2, T and an agent that regulates the expression of one or more of mem183a, Tnfsf11, Tradd, Traf3ip2, Trim35, Trim7, Tssc1, Ttc3, Ube2n, Ufl1, Unkl, Upf1, Vdr, Wdhd1, Wdr48, Wdr95, Wwp1, Ybx1, Zbtb14, Zbtb49, Zbtb7a, and Zmiz1.

[0347] In some embodiments, the additional agent is an agent that modulates the expression of one or more members of module M3 as provided in Example 3, e.g., Akt1, Ankfy1, Apc, Arpc1b, Birc2, Bmil, 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 and an agent that regulates the expression of one or more of: 8, 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.

[0348] G. Methods of Monitoring Response to Treatment In another aspect, the disclosure features a method for monitoring the response of an individual having cancer, an inflammatory disease, an autoimmune disease, or an infectious disease to treatment with (a) an agent that decreases the expression and / or activity of Cebpb; (b) an agent that decreases the expression and / or activity of Traf2; and / or (c) an agent that increases the expression and / or activity of Dido1, the method including: (i) determining the expression level of one or more of Cebpb, Traf2, and Dido1 in a biological sample obtained from the individual at a time point after administration of the agent; and (ii) comparing the expression level of one or more genes in the biological sample to a reference level, thereby monitoring the individual's response to treatment with the agent.

[0349] In another aspect, the disclosure features a method for monitoring the response of an individual having an inflammatory disease, autoimmune disease, or infectious disease to treatment with (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 method including: (i) determining the expression level of one or more of Cebpb, Traf2, and Dido1 in a biological sample obtained from the individual at a time point after administration of the agent; and (ii) comparing the expression level of one or more genes in the biological sample to a reference level, thereby monitoring the individual's response to treatment with the agent.

[0350] In some embodiments, 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 the individual prior to administration of the agent; (ii) the expression level of one or more genes in a reference population; (iii) a pre-assigned expression level for one or more genes; or (iv) the expression level of one or more genes in a biological sample obtained from the individual at an earlier time point after administration of the agent.

[0351] In some embodiments, (a) Cebpb expression and / or activity is increased in a biological sample obtained from the individual compared to a reference level; (b) Traf2 expression and / or activity is increased in a biological sample obtained from the individual compared to a reference level; and / or (c) Dido1 expression and / or activity is decreased in a biological sample obtained from the individual compared to a reference level, and the method further comprises administering one or more additional doses of an agent to the individual, wherein the agent decreases Cebpb expression and / or activity; decreases Traf2 expression and / or activity; and / or increases Dido1 expression and / or activity.

[0352] In some embodiments, (a) Cebpb expression and / or activity is decreased in a biological sample obtained from the individual compared to a reference level; (b) Traf2 expression and / or activity is decreased in a biological sample obtained from the individual compared to a reference level; and / or (c) Dido1 expression and / or activity is increased in a biological sample obtained from the individual compared to a reference level, and the method further comprises administering one or more additional doses of an agent to the individual, wherein the agent increases Cebpb expression and / or activity; increases Traf2 expression and / or activity; and / or decreases Dido1 expression and / or activity.

[0353] VII. Methods of Regulating NFKB1 and / or NFKB2 Processing A. Methods of Treating Cancer, Inflammatory Disease, or Autoimmune Disease In some aspects, the disclosure features a method for treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method including administering to the individual an effective amount of a modulator of the interaction between (a) F-box and WD repeat domain-containing 11 (Fbxw11) and (b) nuclear factor kappa B subunit 1 (Nfkb1) or nuclear factor kappa B subunit 2 (Nfkb2).

[0354] In some aspects, the modulator is a modulator described in Section II herein, e.g., a proteolysis-directed chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antibody-binding fragment thereof that binds to one, two, or all three of Fbxw11, Nfkb1, and Nfkb2), a peptide, a mimetic, or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0355] In some embodiments, the individual has cancer and the modulator is an agent that increases the expression and / or activity of Fbxw11.

[0356] In some embodiments, the individual has an inflammatory or autoimmune disease and the modulator is an agent that decreases the expression and / or activity of Fbxw11.

[0357] In some embodiments, the inflammatory or autoimmune disease is a neurodegenerative disease (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD)), arthritis, allergy, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some embodiments, the inflammatory or autoimmune disease is Crohn's disease. In some embodiments, the inflammatory disease or autoimmune disease is selected from the group consisting of encephalitis, myelitis, meningitis, arachnoiditis, peripheral neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillaritis, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleuritis, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, sialadenitis / parotitis, cheilitis, pulpitis, mandibular inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, appendicitis, appendicitis, proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, medullary tract infections, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, presitis, balanoposthitis, chorioamnionitis, omphalitis, omphalitis, insulitis, hypophysitis, thyroiditis, parathyroiditis, adrenitis, lymphangitis, or lymphadenitis.

[0358] B. Methods for Increasing Nfkb1 and / or Nfkb2 Processing In some aspects, the disclosure features a method for increasing the processing of Nfkb1 and / or Nfkb2 to their active forms, the method including contacting a cell capable of expressing Fbxw11 with an agent that increases the expression and / or activity of Fbxw11.

[0359] An agent that increases the expression and / or activity of Fbxw11 can be, for example, a PROTAC; a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to Fbxw11); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0360] In some embodiments, the cell capable of expressing Fbxw11 is in an individual. In some embodiments, the individual has cancer.

[0361] In some embodiments, processing of Nfkb1 to its active form 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% compared to processing of Nfkb1 to its active form in the individual in the absence of the agent (e.g., increased by 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%, 95% to 100%, or more than 100% compared to processing of Nfkb1 to its active form in the individual in the absence of the agent). In some embodiments, the processing of Nfkb1 to its active form in the individual is increased by at least 10% compared to the processing of Nfkb1 to its active form in the absence of the agent.

[0362] In some embodiments, processing of Nfkb2 to its active form 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% compared to processing of Nfkb2 to its active form in the individual in the absence of the agent (e.g., increased by 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%, 95% to 100%, or more than 100% compared to processing of Nfkb2 to its active form in the individual in the absence of the agent). In some embodiments, the processing of Nfkb2 to its active form in the individual is increased by at least 10% compared to the processing of Nfkb2 to its active form in the absence of the agent.

[0363] C. Methods for reducing Nfkb1 and / or Nfkb2 processing In some aspects, the disclosure features a method for reducing the processing of Nfkb1 and / or Nfkb2 to their active forms, the method including contacting a cell capable of expressing Fbxw11 with an agent that reduces the expression and / or activity of Fbxw11.

[0364] An agent that reduces the expression and / or activity of Fbxw11 can be, for example, a PROTAC; a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to Fbxw11); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0365] In some embodiments, the cell capable of expressing Fbxw11 is in an individual. In some embodiments, the individual has an inflammatory disease or an autoimmune disease. In some embodiments, the inflammatory disease or autoimmune disease is a neurodegenerative disease (e.g., MS, AD, ALS, or PD), arthritis, allergy, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some embodiments, the inflammatory disease or autoimmune disease is Crohn's disease. In some embodiments, the inflammatory disease or autoimmune disease is selected from the group consisting of encephalitis, myelitis, meningitis, arachnoiditis, peripheral neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillaritis, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleuritis, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, sialadenitis / parotitis, cheilitis, pulpitis, mandibular inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, appendicitis, appendicitis, proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, medullary tract infections, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, presitis, balanoposthitis, chorioamnionitis, omphalitis, omphalitis, insulitis, hypophysitis, thyroiditis, parathyroiditis, adrenitis, lymphangitis, or lymphadenitis.

[0366] In some embodiments, processing of Nfkb1 to its active form 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% compared to processing of Nfkb1 to its active form in an individual in the absence of the agent (e.g., reduced by 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% compared to processing of Nfkb1 to its active form in an individual in the absence of the agent). In some embodiments, the processing of Nfkb1 to its active form in the individual is reduced by at least 10% compared to the processing of Nfkb1 to its active form in the absence of the agent.

[0367] In some embodiments, processing of Nfkb2 to its active form 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% compared to processing of Nfkb2 to its active form in an individual in the absence of the agent (e.g., reduced by 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% compared to processing of Nfkb2 to its active form in an individual in the absence of the agent). In some embodiments, the processing of Nfkb2 to its active form in the individual is reduced by at least 10% compared to the processing of Nfkb2 to its active form in the absence of the agent.

[0368] D. Methods of Increasing Immune Responses Directed by Nfkb1 and / or Nfkb2 In another aspect, the disclosure features a method for increasing an immune response directed by Nfkb1 and / or Nfkb2 in an individual (e.g., an individual with cancer), the method including administering to the individual an effective amount of an agent that increases the expression and / or activity of Fbxw11.

[0369] An agent that increases the expression and / or activity of Fbxw11 can be, for example, a PROTAC; a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to Fbxw11); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0370] E. Methods of Increasing Immune Responses Directed by Nfkb1 and / or Nfkb2 In another aspect, the disclosure features a method for reducing an immune response directed by Nfkb1 and / or Nfkb2 in an individual (e.g., an individual having an inflammatory disease or an autoimmune disease), the method including administering to the individual an effective amount of an agent that reduces the expression and / or activity of Fbxw11.

[0371] An agent that reduces the expression and / or activity of Fbxw11 can be, for example, a PROTAC; a small molecule; an antibody or antigen-binding fragment thereof (e.g., a bis-Fab, Fv, Fab, Fab'-SH, F(ab')2, diabody, linear antibody, scFv, scFab, VH domain, or VHH domain) (e.g., an antibody or antigen-binding fragment thereof that binds to Fbxw11); a peptide; a mimetic; or an inhibitory nucleic acid (e.g., an ASO or siRNA).

[0372] In some embodiments, the inflammatory or autoimmune disease is a neurodegenerative disease (e.g., MS, AD, ALS, or PD), arthritis, an allergy, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. In some embodiments, the inflammatory or autoimmune disease is Crohn's disease. In some embodiments, the inflammatory disease or autoimmune disease is selected from the group consisting of encephalitis, myelitis, meningitis, arachnoiditis, peripheral neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillaritis, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleuritis, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, sialadenitis / parotitis, cheilitis, pulpitis, mandibular inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, appendicitis, appendicitis, proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, osteochondritis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, medullary tract infections, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, presitis, balanoposthitis, chorioamnionitis, omphalitis, omphalitis, insulitis, hypophysitis, thyroiditis, parathyroiditis, adrenitis, lymphangitis, or lymphadenitis.

[0373] F. Combination Therapy Any of the methods in Sections VII(A)-VII(E) may further include administering one or more additional agents to the individual or to cells 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).

[0374] In some embodiments, the additional agent is an agent that modulates the expression of one or more members of module M5 as presented in Example 3, such as Acaca, Ambla1, 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, Kctd14, Kctd15, Kctd16, Kctd17, Kctd18, Kctd19, Kctd20, Kctd21, Kctd22, Kctd23, Kctd24, Kctd25, Kctd26, Kctd27, Kctd28, Kctd2 ...9, Kctd20, Kctd21, Kctd22, Kctd23, Kctd24, Kctd25, Kctd26, 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.

[0375] In some embodiments, the additional agent is an agent that modulates the expression of one or more members of module M6 as provided in Example 3, such as 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 and an agent that regulates the expression of one or more of 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.

[0376] G. Methods of Monitoring Response to Treatment In another aspect, the disclosure features 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 including: (i) determining the expression level of an activated form of one or both of Nfkb1 and Nfkb2 in a biological sample obtained from the individual at a time point after administration of the modulator; and (ii) comparing the expression level of an activated form of one or both of Nfkb1 and Nfkb2 in the biological sample to a reference level, thereby monitoring the individual's response to treatment with the modulator.

[0377] In some embodiments, the reference level is selected from the group consisting of: (i) the expression level of one or both genes in a biological sample obtained from the individual prior to administration of the modulator; (ii) the expression level of one or both genes in a reference population; (iii) a pre-assigned expression level for one or both genes; or (iv) the expression level of one or both genes in a biological sample obtained from the individual at an earlier time point after administration of the modulator.

[0378] In some aspects, the individual has cancer and the expression level of activated forms of one or both of Nfkb1 and Nfkb2 is decreased in a biological sample obtained from the individual compared to a reference level, and the method further comprises 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.

[0379] In some aspects, the individual has an inflammatory or autoimmune disease, and the expression level of activated forms of one or both of Nfkb1 and Nfkb2 is increased in a biological sample obtained from the individual compared to a baseline level, and the method further comprises administering one or more additional doses of a modulator to the individual, wherein the modulator is an agent that decreases the expression and / or activity of Fbxw11.

[0380] VIII. Cell therapy A. Methods of Treating Cancer, Inflammatory Disease, or Autoimmune Disease Using Cellular Therapy In some aspects, the disclosure features a method for treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method including administering to an individual a co-functional gene module comprising: (a) Aamp, Bop1, Cirh1a, Dcaf13, Grb2, Myc, Nle1, Nol10, Pak1ip1, Ptpn11, module M1, including Rack1, Raf1, Rrp9, Taf5, Tbl3, Uhrf1, Utp15, Utp18, Vprbp, Wdr3, Wdr36, Wdr43, Wdr5, Wdr74, and Wdr75; (b) Ago2, Ahr, Anapc13, Bach1, Baz1a, Bid, Bptf, Brca1, Brwd3, Btbd1, Cblc, Ccnf, Cdc27, Cntn4, Copa, Copb2, Coro1a, Cpne9, Cul4b, Ddb1, Dido1, E4f1, Ecel1, Fbxl14, Fbx l5, Fbxo11, Fbxo42, Fzr1, Gemin5, Gm10697, Gm9117, Gtf2h2, Gtf3c1, Hdac4, Hectd1, I ft122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23, Klhl3, Kmt2b, LOC10086178 4, module M2 containing 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)Akt1, Ankfy1, Apc, Arpc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, 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, Pik3r 4, module M3 containing 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 contains Cdc40, Ddx41, Plrg1, Ppil2, Ppwd1, Prpf19, Prpf4, Sart1, Smu1, Snrnp40, and Wdr70; (e) 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, Lztr module M5, including 1, 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)Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fbxw11, Fus, Gm9840, Hif1 a, Huwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, Ranbp2, Rbbp6, Rbck1, R Module M6 includes bx1, 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 administering to the individual an effective amount of a cell therapy comprising alterations in at least two of the genes within one or more of:

[0381] For example, the cell may have: (1) alterations in at least two of the genes in module M1 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in module M1); (2) alterations in at least two of the genes in module M2 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in module M2); or (3) alterations in at least two of the genes in module M3 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in module M3). (4) alterations in at least two of the genes of module M4 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes of module M4); (5) alterations in at least two of the genes of module M5 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes of module M5); or (6) alterations in at least two of the genes of module M6 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes of module M6).

[0382] In some embodiments, the cell includes alterations in at least two genes in a first module and one or more genes in a second module, e.g., at least two of the genes in module M1 and at least one of the genes in any one of modules M2-M6.

[0383] In some embodiments, the cell includes alterations in at least two genes in a first module and at least two genes in a second module, e.g., at least two of the genes in module M1 and at least two of the genes in any one of modules M2-M6.

[0384] In some aspects, the disclosure features a method for treating cancer, an inflammatory disease, or an autoimmune disease in an individual, the method including translating a gene module comprising: (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, 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, Rps3a1, Rps4x, Rps5, Rps6, Rps7, Rps8, Rps9, Rpsa, Rptor, Sgk1, Ssr4, Tab1, Taf5, Tpt1, Uhrf1, Uqcrh, Utp15, Wdr3, Wdr36, Wdr43, Wdr5, and Zbtb25; (b)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, Cxcl3, Cyb5a Dap, Dars, Dck, Ddb1, Ddit3, Egr2, Eif3f, Eif3i, Ep3 0, Esd, Fbxl5, Fbxw11, Gbe1, Gclm, Gdap10, Gm9840, Gss. Gstm1, H3f3b, Hmox1, Hvcn1, Il1f9, Inhba, Keap1, Lipa, Lmo4, Map3k7, Mcl1, Mcoln2, Met, Mgst2, Mmp12, Mmp19. Mmp8, Mylip, Nampt, Nedd8, Nf1, Npy, Nrp1, Nup43, Nupr1, Paf1, Pf4, Pgd, Phlda1, Pla2g7, Plet1, Ppfibp2, Prdx 1. Prdx6, Preb, Prkcb, Procr, Ptgr1, Ptpn1, Raf1, Rbx1, Rhob, Rnasel, Rnf128, Runx2, Sdc4, Sec13, Seh1l, Skp1 a, Slc43a2, Slc48a1, Slc7a11, Slpi, Smad2, Srxn1, Taldo1, Tarm1, Thbs1, Tlr2, Tlr4, Tma16, Tpm4, Traf2, and Traf 5, Traf6, Trip12, Tubb2a, Txnrd1, Ube2d3, Ube2n, Ubr5 Uchl1, Upf1, Wdr43, Wdr61, Zbtb17, and Zyx. (c)Acp5, Ankfy1, Arpc1b, Atp6v0d2, Bptf, Brap, C5ar1, Ccdc88a, Cd14, Cd36, Cd63, Cebpb, Ch d4, Clec4d, Clec5a, Cpd, Creg1, Ctsb, Ctsz, Cul3, Ddhd1, Dnmt3a, Egr2, Emb, F630028O10Rik, Fabp5, Fam46c, Fbxo42, Fcgr2b, Fn1, Foxo3, Fpr1, Ftl1, Gadd45a, Glrx, Gpnmb, Gpr84, Huwe1, Icam1, Id1, Il1f9, Kctd10, Keap1, Klhl6, Lcn2, Lgals1, Lgals3, Lgmn, Lipa, Lpcat2, Ly6c2, M arch6, Metrnl, Mgll, Mt1, Mtor, Myof, Naaa, Naca, Nf1, Paf1, Phlda1, Pid1, Pik3r4, Pld3, Ple t1, Plk2, Pou2f2, Pparg, Prdx5, Psap, Ptpn11, Rab3il1, Rela, Rfwd2, Rnase2a, S100a1, S100a 11, gene set 3 including S100a8, Saa3, Sdc3, Serpinb2, Slamf7, Snx18, Sod2, Spata13, Stap1, Strap, Tab1, Tceb2, Tgfbi, Thbs1, Trem1, Upf1, Upp1, Vat1, Wdfy3, Wfdc21,2010005H15Rik, and Zbtb25; (d)AC160336.1, Actb, Actg1, Ankfy1, Arhgdib, Bptf, Brap, Bri3, Ccr 2, Ccr5, Cd274, Cdkn1a, Cfl1, Chd4, Clec4a2, Cup, Crown1a, Cotl1, Cri p1, Cul1, Cul3, Dars, Ddhd1, Ddit3, Ear2, Eif3f, Eif3i, Ep300, Fbxw1 1. Flna, Gbp2, Gbp5, Grb2, Gtf3c1, H2-D1, H2-K1, Huwe1, Ifi27l2a, Il1 rn, Keap1, Klk1b1, Lcp1, Lgals1, Lpl, Lrr1, Lsp1, Malat1, Marksl1 Med8, Mgll, Mndal, Mtor, Naca, Nedd8, Nf1, Paf1, Pfn1, Pik3r4, Pten, P tma, Ptpn11, Rack1, Rela, Rnf20, Sdc4, Skp1a, Taf3, Taf5, Tlr4, Tmsb 4x, Ubb, Ube2i, Upf1, Vhl, Wdfy3, Wdr43, Wdr82, and Wfdc17. (e) Gene set 5 comprising AA467197, AW112010, Abcg1, Acod1, Bcl2a1b, Bcl2a1d, Cav1, Ccl17, Ccl3, Ccl4, Cd14, Cd200r1, Cd300lf, Cdkn1a, Cebpb, Cflar, Chd4, Clec4e, Clic4, Copa, Cpd, Cpeb4, Cul1, Cul3, Cxcl1, Cxcl2, Cxcl3, Ehd1, Ep300, Fam102b, Fam20c, Fbxw11, Gda, Gpr84, Hist1h1c, Hivep3, Ikbke, Ikbkg, Il12b, Il1a, Il1b, Il6, Ing3, Inhba, Kctd21, Klf4, Laptm5, Mafb, Malat1, Malt1, Marcks, Marcksl1, Marco, Met, Mtpn, Nabp1, Nedd8, Nfkb1, Nfkbiz, Nlrp3, Nrp2, Nup62, Ogt, Paf1, Plek, Plrg1, Ppfia3, Prpf19, Ptgs2, Ptx3, Rassf4, Rbx1, Rela, Rfwd2, Rnf31, Serpinb2, Sh3bp5, Skp1a, Slc7a11, 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)AA467197, Ahr, Akt1, Ankfy1, Axl, Bhlhe40, Bhlhe41, Btg1, Ccl17, Ccl22, Ccr2, Cd40, C d52, Cd74, Cebpb, Chd4, Clec4e, Clec4n, Clic4, Cst3, Cstf1, Ctsb, Ctsd, Cxcl16, Dcstamp, E gr2, Etv3, Fabp4, Fabp5, Fam20c, Fbxw7, Fbxw9, Foxo3, Fpr1, Fth1, Ftl1, Gbp2, Gbp5, Gm2a, G nb1, Gnb2, Grb2, Grk3, Gsk3b, H2-Aa, H2-Ab1, Hmox1, Igf1, Il4i1, Irf4, Itgax, Jak2, Jund, K Gene set 6 includes cmf1, Klhl6, Kmt2d, Lgals1, Lyz2, March6, Mgl2, Mmp12, Mtor, Myc, Ndufa4, 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)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, Inhba, Keap1, Km gene set 7, including t2d, 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) 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, Eif3f, Eif3i. Erp29, Fbxw7, Fth1, Ftl1, Gm9840, Grb2, Gtf3c1, Herpud1, Hif1a, Hnrnpa3, Hsp90b1, Hspa5, Ift20 Keap1, Kmt2d, Krtcap2, Lgals3, Lrr1, Lyz2, Manf, Map3k7, Mthfd2, Mtor, Myc, Naca, Nedd8, Nf1, No l10, 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, Se rf2, Serp1, Sf3b5, Spcs2, Ssr3, Surf4, Syvn1, Tceal9, Tceb1, Tceb2, Timm13, Tpt1, Tram1, Trp53. Ube2f, Ufm1, Uqcrq, Utp15, Vcp, Vhl, Vprbp, Wdr3 6, Wdr43, Wdr5, Wdr74, Wdr75, and Xbp1. (i)Acod1, Adam8, Atp5g3, Brap, C3ar1, Ccl2, Ccl3, Ccl4, Ccl7, Ccnd1, Cd300ld, Cd63, Ch25h, Chd 4. Chil3, Crip1, Ctsb, Ctsl, Cul1, Cul3, Cxcl1, Cyp51, Det1, Ear2, Egr2, F10, Fbxo42, Fbxw11, Ffa r2, Fpr2, Phyb, Gas7, Gm9840, Gnb2, Gpnmb, Grb2, Gsk3b, Hmgcs1, Huwe1, Ifitm3, Il1f9, Itgam, Jun. Kctd12, Kctd5, Keap1, Klhdc4, Kmt2c, Kmt2d, Lgals1, Lgals3, Lmna, Lmo4, Lrpap1, Ly6c2, Lztr1, M of March6, Mcemp1, Mmp12, Mmp13, Mmp8, Msr1, Mtor, Naaa, Naca, Nf1, Nfkbiz, Npc2, Npy, Paf1, Pdp n, Pf4, Plet1, Pparg, Prkcd, Pten, Ptgs2, Ptpn1, Ptpn11, Ptprc, Ptx3, Rbbp5, Rela, Rfwd2, Rheb, R ptor, S100a6, Saa3, Scap, Scd2, Serpinb2, Serpinb6a, Sgk1, Slc7a11, Smad2, Srgn, Syk, Syngr1, T imp2, Trem2, Ube2h, Ube2i, Ucp2, Vasp, Vhl, Wdr2 6, Wfdc21, Ybx1, Zbtb7a, and Zfp36l2. (j)Acaca, Ak4, Aldoa, Aldoc, Anapc13, Anxa2, Arih2, Arnt, Basp1, Bnip3l, Bsg, C3ar 1, Ccl9, Cd52, Chil3, Copa, Cul2, Cul3, Cul5, Egr2, Eif3i, Eif4ebp1, Emilin2, Eno1 Ep300, Fam162a, Gapdh, Gbe1, Gpi1, Gsn, Herpud1, Hif1a, Higd1a, Hilpda, Hk1, Hk2, H mox1, Huwe1, Ier3, Kctd10, Klk1b1, Ldha, Lgals3, Lipa, Lmo4, Lpcat2, Lyz2, March6 Mif, Mt1, Mt2, Mtor, Myc, Ndufv3, Nf1, Pdk1, Pfkl, Pgam1, Pgk1, Pgm2, Pkm, Prdx1, Pre lid1, Ptpn1, Ptpn11, Rbpj, Rfwd2, Rilpl2, Rnase2a, Sacs, Scd2, Sdc3, Sdc4, Sec13 lamf9, Slc16a3, Slc2a1, Slc7a2, Smu1, Socs3, Strap, Tarm1, Tceb1, Tceb2, Tgm2, Tlr 4, Tpi1, Trf, Ube2f, Vhl, Vim, Wdr43, Wdr82, Wfdc17, and 2010005H15Rik. (k)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, I l4i1, Inhba, Itgax, Itgb2, Kctd10, Klk1b11, Lpl, Maf, Marcks, Marcksl1, Med8, Met, Mmp gene set 12, including 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, Tnfaip2, Traf3, Ufm1, Upp1, Wdr5, Wdr70, Wdr82, Wfdc17, Wfdc21, 0610012G03Rik, Zbtb7a, and Zyx; (l) Ambra1, Aplp2, 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, Nupr 1, gene set 12 including 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)Ankfy1, Anxa1, Anxa5, Aph1c, Brap, C3ar1, Ccnd2, Ccr1, Cd300lf, Cd38, Cd68, Cd9, Cdc27, Cdc40, Cebpb, Chd4, Chst11, Clec4e, Creb5, Cul1, Cul3, Cxcl3, Cyba, Dstn, Eif 3f, Eif3i, Emp1, Epha4, Fam102b, Fam46a, Fbxw11, Fn1, Foxo3, Ftl1, Furin, Gas7, Gdf1 5, Grb2, H2-K1, Huwe1, Icam1, Il7r, Inhba, Keap1, Klhdc4, Klk1b11, Lgals3, Lpl, Ly6c 2, gene set 13 including Lyz2, March6, Mbnl1, Mmp14, Mmp8, Ms4a7, Naca, Neat1, Nf1, Nrp2, Plin2, 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)AC160336.1, Adgre1, Adgre4, Adgrl2, Anxa1, B2m, C1qb, C3, Car4, Ccdc88a, Ccl6, C d52, 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, Marcks, Mcub, Med8, M Gene set 14 includes pc1, 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)AC160336.1, Adgre1, Ahnak, Alcam, Aprt, Bcl2l11, Blvrb, Brap, Bub3, C1qb, C1qc , C3ar1, Cd300c2, Cd33, Cd68, Cdc40, Cebpb, Chchd2, Clec12a, Clec4n, Copa, Csf1r, Ct sz, Cul3, Cul5, Cyba, Ddx41, Dstn, Egr2, Ep300, F7, Fbxw7, Fcer1g, Fcgr2b, Gmfg, Gngt 2, Gpr84, Hsp90aa1, Huwe1, Igf1, Kat6a, Kctd12b, Kdm5c, Keap1, Kmt2d, Lst1, Mmp14, M Gene set 15 includes peg1, Myc, Naca, P2ry14, Paf1, Pirb, Plrg1, Pou2f2, Pparg, Ppil2, Ppwd1, Prkcd, Prpf19, Prpf4, Ptpn1, Ptpn18, Rack1, Rbbp5, Rnf20, Rnf40, Rnf7, Rps27l, Sat1, Serpinb2, Smu1, Socs3, Spp1, Taf5, Tank, Tceb1, Tceb2, Tgm2, Tnfsf15, Traf2, Trem2, Tyrobp, Ufm1, Vcan, Wdr1, Wdr33, Wdr43, Wdr5, Wdr61, Wdr70, Wdr82, Wfdc21, and Ybx1. The method includes administering to the individual an effective amount of a cell therapy comprising cells that include alterations in at least two of the genes within one or more of the following:

[0385] For example, the cell may have (1) alterations in at least two of the genes in gene set 1 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 1); (2) alterations in at least two of the genes in gene set 2 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 2); (3) alterations in at least two of the genes in gene set 3 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 3). (4) alterations in at least two of the genes in gene set 4 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 4); (5) alterations in at least two of the genes in gene set 5 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 5); (6) alterations in at least two of the genes in gene set 6 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 6); (7) alterations in at least two of the genes in gene set 7 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 7), (8) alterations in at least two of the genes in gene set 8 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 8); (9) alterations in at least two of the genes in gene set 9 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 9); (10) (11) alterations in at least two of the genes in gene set 10 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 10); (12) alterations in at least two of the genes in gene set 12 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 12);(13) alterations in at least two of the genes in gene set 13 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 13); (14) alterations in at least two of the genes in gene set 14 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 14); or (15) alterations in at least two of the genes in gene set 15 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 15).

[0386] In some embodiments, the cell comprises an alteration in at least two genes in a first gene set and one or more genes in a second gene set, e.g., an alteration in at least two of the genes in gene set 1 and at least one gene in any one of gene sets 2-15.

[0387] In some embodiments, the cell includes alterations in at least two genes in the first module and at least two genes in the second module, e.g., at least two of the genes in gene set 1 and at least two of the genes in any one of gene sets 2-15.

[0388] The alterations can be loss-of-function mutations (e.g., mutations resulting in reduced or eliminated protein function, including deletions) or gain-of-function mutations (e.g., mutations resulting in increased gene function, including gene duplications). For example, a cell containing alterations in two of the genes of module M1 can contain loss-of-function mutations in both genes; can contain gain-of-function mutations in both genes; or can contain a loss-of-function mutation in the first gene and a gain-of-function mutation in the second gene. In some embodiments, at least one of the alterations is a loss-of-function alteration. In some embodiments, at least one of the alterations is a gain-of-function alteration.

[0389] In some aspects, the cell therapy is dendritic cell therapy, macrophage cell 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.

[0390] B. Modified Cells In another aspect, the present disclosure provides the following co-functional gene modules: (a) Module M1, including 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) Ago2, Ahr, Anapc13, Bach1, Baz1a, Bid, Bptf, Brca1, Brwd3, Btbd1, Cblc, Ccnf, Cdc27, Cntn4, Copa, Copb2, Coro1a, Cpne9, Cul4b, Ddb1, Dido1, E4f1, Ecel1, Fbxl14, Fbx l5, Fbxo11, Fbxo42, Fzr1, Gemin5, Gm10697, Gm9117, Gtf2h2, Gtf3c1, Hdac4, Hectd1, I ft122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23, Klhl3, Kmt2b, LOC10086178 4, module M2 containing 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)Akt1, Ankfy1, Apc, Arpc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, 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, Pik3r 4, module M3 containing 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 contains Cdc40, Ddx41, Plrg1, Ppil2, Ppwd1, Prpf19, Prpf4, Sart1, Smu1, Snrnp40, and Wdr70; (e) 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, Lztr module M5, including 1, 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)Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fbxw11, Fus, Gm9840, Hif1 a, Huwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, Ranbp2, Rbbp6, Rbck1, R Module M6 includes bx1, 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 and a genetically modified isolated cell comprising an alteration in at least two of the genes within one or more of:

[0391] For example, the genetically modified isolated cells may contain: (1) alterations in at least two of the genes in module M1 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in module M1); (2) alterations in at least two of the genes in module M2 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in module M2); (3) alterations in at least two of the genes in module M3 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in module M3). (4) alterations in at least two of the genes of module M4 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes of module M4); (5) alterations in at least two of the genes of module M5 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes of module M5); or (6) alterations in at least two of the genes of module M6 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes of module M6).

[0392] In some embodiments, the genetically modified isolated cell comprises alterations in at least two genes in a first module and one or more genes in a second module, e.g., alterations in at least two of the genes in module M1 and at least one of the genes in any one of modules M2-M6.

[0393] In some embodiments, the genetically modified isolated cell comprises alterations in at least two genes in a first module and at least two genes in a second module, e.g., alterations in at least two of the genes in module M1 and at least two of the genes in any one of modules M2-M6.

[0394] In another aspect, the present disclosure provides 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, 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, Rps3a1, Rps4x, Rps5, Rps6, Rps7, Rps8, Rps9, Rpsa, Rptor, Sgk1, Ssr4, Tab1, Taf5, Tpt1, Uhrf1, Uqcrh, Utp15, Wdr3, Wdr36, Wdr43, Wdr5, and Zbtb25; (b)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, Cxcl3, Cyb5a Dap, Dars, Dck, Ddb1, Ddit3, Egr2, Eif3f, Eif3i, Ep3 0, Esd, Fbxl5, Fbxw11, Gbe1, Gclm, Gdap10, Gm9840, Gss. Gstm1, H3f3b, Hmox1, Hvcn1, Il1f9, Inhba, Keap1, Lipa, Lmo4, Map3k7, Mcl1, Mcoln2, Met, Mgst2, Mmp12, Mmp19. Mmp8, Mylip, Nampt, Nedd8, Nf1, Npy, Nrp1, Nup43, Nupr1, Paf1, Pf4, Pgd, Phlda1, Pla2g7, Plet1, Ppfibp2, Prdx 1. Prdx6, Preb, Prkcb, Procr, Ptgr1, Ptpn1, Raf1, Rbx1, Rhob, Rnasel, Rnf128, Runx2, Sdc4, Sec13, Seh1l, Skp1 a, Slc43a2, Slc48a1, Slc7a11, Slpi, Smad2, Srxn1, Taldo1, Tarm1, Thbs1, Tlr2, Tlr4, Tma16, Tpm4, Traf2, and Traf 5, Traf6, Trip12, Tubb2a, Txnrd1, Ube2d3, Ube2n, Ubr5 Uchl1, Upf1, Wdr43, Wdr61, Zbtb17, and Zyx. (c)Acp5, Ankfy1, Arpc1b, Atp6v0d2, Bptf, Brap, C5ar1, Ccdc88a, Cd14, Cd36, Cd63, Cebpb, Ch d4, Clec4d, Clec5a, Cpd, Creg1, Ctsb, Ctsz, Cul3, Ddhd1, Dnmt3a, Egr2, Emb, F630028O10Rik, Fabp5, Fam46c, Fbxo42, Fcgr2b, Fn1, Foxo3, Fpr1, Ftl1, Gadd45a, Glrx, Gpnmb, Gpr84, Huwe1, Icam1, Id1, Il1f9, Kctd10, Keap1, Klhl6, Lcn2, Lgals1, Lgals3, Lgmn, Lipa, Lpcat2, Ly6c2, M arch6, Metrnl, Mgll, Mt1, Mtor, Myof, Naaa, Naca, Nf1, Paf1, Phlda1, Pid1, Pik3r4, Pld3, Ple t1, Plk2, Pou2f2, Pparg, Prdx5, Psap, Ptpn11, Rab3il1, Rela, Rfwd2, Rnase2a, S100a1, S100a 11, gene set 3 including S100a8, Saa3, Sdc3, Serpinb2, Slamf7, Snx18, Sod2, Spata13, Stap1, Strap, Tab1, Tceb2, Tgfbi, Thbs1, Trem1, Upf1, Upp1, Vat1, Wdfy3, Wfdc21,2010005H15Rik, and Zbtb25; (d)AC160336.1, Actb, Actg1, Ankfy1, Arhgdib, Bptf, Brap, Bri3, Ccr 2, Ccr5, Cd274, Cdkn1a, Cfl1, Chd4, Clec4a2, Cup, Crown1a, Cotl1, Cri p1, Cul1, Cul3, Dars, Ddhd1, Ddit3, Ear2, Eif3f, Eif3i, Ep300, Fbxw1 1. Flna, Gbp2, Gbp5, Grb2, Gtf3c1, H2-D1, H2-K1, Huwe1, Ifi27l2a, Il1 rn, Keap1, Klk1b1, Lcp1, Lgals1, Lpl, Lrr1, Lsp1, Malat1, Marksl1 Med8, Mgll, Mndal, Mtor, Naca, Nedd8, Nf1, Paf1, Pfn1, Pik3r4, Pten, P tma, Ptpn11, Rack1, Rela, Rnf20, Sdc4, Skp1a, Taf3, Taf5, Tlr4, Tmsb 4x, Ubb, Ube2i, Upf1, Vhl, Wdfy3, Wdr43, Wdr82, and Wfdc17. (e) Gene set 5 comprising AA467197, AW112010, Abcg1, Acod1, Bcl2a1b, Bcl2a1d, Cav1, Ccl17, Ccl3, Ccl4, Cd14, Cd200r1, Cd300lf, Cdkn1a, Cebpb, Cflar, Chd4, Clec4e, Clic4, Copa, Cpd, Cpeb4, Cul1, Cul3, Cxcl1, Cxcl2, Cxcl3, Ehd1, Ep300, Fam102b, Fam20c, Fbxw11, Gda, Gpr84, Hist1h1c, Hivep3, Ikbke, Ikbkg, Il12b, Il1a, Il1b, Il6, Ing3, Inhba, Kctd21, Klf4, Laptm5, Mafb, Malat1, Malt1, Marcks, Marcksl1, Marco, Met, Mtpn, Nabp1, Nedd8, Nfkb1, Nfkbiz, Nlrp3, Nrp2, Nup62, Ogt, Paf1, Plek, Plrg1, Ppfia3, Prpf19, Ptgs2, Ptx3, Rassf4, Rbx1, Rela, Rfwd2, Rnf31, Serpinb2, Sh3bp5, Skp1a, Slc7a11, 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)AA467197, Ahr, Akt1, Ankfy1, Axl, Bhlhe40, Bhlhe41, Btg1, Ccl17, Ccl22, Ccr2, Cd40, C d52, Cd74, Cebpb, Chd4, Clec4e, Clec4n, Clic4, Cst3, Cstf1, Ctsb, Ctsd, Cxcl16, Dcstamp, E gr2, Etv3, Fabp4, Fabp5, Fam20c, Fbxw7, Fbxw9, Foxo3, Fpr1, Fth1, Ftl1, Gbp2, Gbp5, Gm2a, G nb1, Gnb2, Grb2, Grk3, Gsk3b, H2-Aa, H2-Ab1, Hmox1, Igf1, Il4i1, Irf4, Itgax, Jak2, Jund, K Gene set 6 includes cmf1, Klhl6, Kmt2d, Lgals1, Lyz2, March6, Mgl2, Mmp12, Mtor, Myc, Ndufa4, 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)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, Inhba, Keap1, Km gene set 7, including t2d, 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) 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, Eif3f, Eif3i. Erp29, Fbxw7, Fth1, Ftl1, Gm9840, Grb2, Gtf3c1, Herpud1, Hif1a, Hnrnpa3, Hsp90b1, Hspa5, Ift20 Keap1, Kmt2d, Krtcap2, Lgals3, Lrr1, Lyz2, Manf, Map3k7, Mthfd2, Mtor, Myc, Naca, Nedd8, Nf1, No l10, 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, Se rf2, Serp1, Sf3b5, Spcs2, Ssr3, Surf4, Syvn1, Tceal9, Tceb1, Tceb2, Timm13, Tpt1, Tram1, Trp53. Ube2f, Ufm1, Uqcrq, Utp15, Vcp, Vhl, Vprbp, Wdr3 6, Wdr43, Wdr5, Wdr74, Wdr75, and Xbp1. (i)Acod1, Adam8, Atp5g3, Brap, C3ar1, Ccl2, Ccl3, Ccl4, Ccl7, Ccnd1, Cd300ld, Cd63, Ch25h, Chd 4. Chil3, Crip1, Ctsb, Ctsl, Cul1, Cul3, Cxcl1, Cyp51, Det1, Ear2, Egr2, F10, Fbxo42, Fbxw11, Ffa r2, Fpr2, Phyb, Gas7, Gm9840, Gnb2, Gpnmb, Grb2, Gsk3b, Hmgcs1, Huwe1, Ifitm3, Il1f9, Itgam, Jun. Kctd12, Kctd5, Keap1, Klhdc4, Kmt2c, Kmt2d, Lgals1, Lgals3, Lmna, Lmo4, Lrpap1, Ly6c2, Lztr1, M of March6, Mcemp1, Mmp12, Mmp13, Mmp8, Msr1, Mtor, Naaa, Naca, Nf1, Nfkbiz, Npc2, Npy, Paf1, Pdp n, Pf4, Plet1, Pparg, Prkcd, Pten, Ptgs2, Ptpn1, Ptpn11, Ptprc, Ptx3, Rbbp5, Rela, Rfwd2, Rheb, R ptor, S100a6, Saa3, Scap, Scd2, Serpinb2, Serpinb6a, Sgk1, Slc7a11, Smad2, Srgn, Syk, Syngr1, T imp2, Trem2, Ube2h, Ube2i, Ucp2, Vasp, Vhl, Wdr2 6, Wfdc21, Ybx1, Zbtb7a, and Zfp36l2. (j)Acaca, Ak4, Aldoa, Aldoc, Anapc13, Anxa2, Arih2, Arnt, Basp1, Bnip3l, Bsg, C3ar 1, Ccl9, Cd52, Chil3, Copa, Cul2, Cul3, Cul5, Egr2, Eif3i, Eif4ebp1, Emilin2, Eno1 Ep300, Fam162a, Gapdh, Gbe1, Gpi1, Gsn, Herpud1, Hif1a, Higd1a, Hilpda, Hk1, Hk2, H mox1, Huwe1, Ier3, Kctd10, Klk1b1, Ldha, Lgals3, Lipa, Lmo4, Lpcat2, Lyz2, March6 Mif, Mt1, Mt2, Mtor, Myc, Ndufv3, Nf1, Pdk1, Pfkl, Pgam1, Pgk1, Pgm2, Pkm, Prdx1, Pre lid1, Ptpn1, Ptpn11, Rbpj, Rfwd2, Rilpl2, Rnase2a, Sacs, Scd2, Sdc3, Sdc4, Sec13 lamf9, Slc16a3, Slc2a1, Slc7a2, Smu1, Socs3, Strap, Tarm1, Tceb1, Tceb2, Tgm2, Tlr 4, Tpi1, Trf, Ube2f, Vhl, Vim, Wdr43, Wdr82, Wfdc17, and 2010005H15Rik. (k)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, I l4i1, Inhba, Itgax, Itgb2, Kctd10, Klk1b11, Lpl, Maf, Marcks, Marcksl1, Med8, Met, Mmp gene set 12, including 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, Tnfaip2, Traf3, Ufm1, Upp1, Wdr5, Wdr70, Wdr82, Wfdc17, Wfdc21, 0610012G03Rik, Zbtb7a, and Zyx; (l) Ambra1, Aplp2, 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, Nupr 1, gene set 12 including 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)Ankfy1, Anxa1, Anxa5, Aph1c, Brap, C3ar1, Ccnd2, Ccr1, Cd300lf, Cd38, Cd68, Cd9, Cdc27, Cdc40, Cebpb, Chd4, Chst11, Clec4e, Creb5, Cul1, Cul3, Cxcl3, Cyba, Dstn, Eif 3f, Eif3i, Emp1, Epha4, Fam102b, Fam46a, Fbxw11, Fn1, Foxo3, Ftl1, Furin, Gas7, Gdf1 5, Grb2, H2-K1, Huwe1, Icam1, Il7r, Inhba, Keap1, Klhdc4, Klk1b11, Lgals3, Lpl, Ly6c 2, gene set 13 including Lyz2, March6, Mbnl1, Mmp14, Mmp8, Ms4a7, Naca, Neat1, Nf1, Nrp2, Plin2, 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)AC160336.1, Adgre1, Adgre4, Adgrl2, Anxa1, B2m, C1qb, C3, Car4, Ccdc88a, Ccl6, C d52, 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, Marcks, Mcub, Med8, M Gene set 14 includes pc1, 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)AC160336.1, Adgre1, Ahnak, Alcam, Aprt, Bcl2l11, Blvrb, Brap, Bub3, C1qb, C1qc , C3ar1, Cd300c2, Cd33, Cd68, Cdc40, Cebpb, Chchd2, Clec12a, Clec4n, Copa, Csf1r, Ct sz, Cul3, Cul5, Cyba, Ddx41, Dstn, Egr2, Ep300, F7, Fbxw7, Fcer1g, Fcgr2b, Gmfg, Gngt 2, Gpr84, Hsp90aa1, Huwe1, Igf1, Kat6a, Kctd12b, Kdm5c, Keap1, Kmt2d, Lst1, Mmp14, M Gene set 15 includes peg1, Myc, Naca, P2ry14, Paf1, Pirb, Plrg1, Pou2f2, Pparg, Ppil2, Ppwd1, Prkcd, Prpf19, Prpf4, Ptpn1, Ptpn18, Rack1, Rbbp5, Rnf20, Rnf40, Rnf7, Rps27l, Sat1, Serpinb2, Smu1, Socs3, Spp1, Taf5, Tank, Tceb1, Tceb2, Tgm2, Tnfsf15, Traf2, Trem2, Tyrobp, Ufm1, Vcan, Wdr1, Wdr33, Wdr43, Wdr5, Wdr61, Wdr70, Wdr82, Wfdc21, and Ybx1. The present invention provides isolated genetically modified cells comprising alterations in at least two of the genes in one or more of:

[0395] For example, the genetically modified isolated cells may contain: (1) alterations in at least two of the genes in gene set 1 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 1); (2) alterations in at least two of the genes in gene set 2 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 2); (3) alterations in at least two of the genes in gene set 3 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 3). (4) alterations in at least two of the genes in gene set 4 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 4); (5) alterations in at least two of the genes in gene set 5 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 5); (6) alterations in at least two of the genes in gene set 6 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 6); (7) alterations in at least two of the genes in gene set 7 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 7); (8) alterations in at least two of the genes in gene set 8 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 8); (9) alterations in at least two of the genes in gene set 9 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 9). (10) alterations in at least two of the genes in gene set 10 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 10); (11) alterations in at least two of the genes in gene set 11 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 11);(12) alterations in at least two of the genes in gene set 12 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 12); (13) alterations in at least two of the genes in gene set 13 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 13); (14) alterations in at least two of the genes in gene set 14 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 14); or (15) alterations in at least two of the genes in gene set 15 (e.g., alterations in 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more of the genes in gene set 15).

[0396] In some embodiments, the genetically modified isolated cell comprises an alteration in at least two genes in a first gene set and one or more genes in a second gene set, e.g., an alteration in at least two of the genes in gene set 1 and at least one gene in any one of gene sets 2-15.

[0397] In some embodiments, the genetically modified isolated cell comprises alterations in at least two genes in a first module and at least two genes in a second module, e.g., at least two of the genes in gene set 1 and at least two of the genes in any one of gene sets 2-15.

[0398] The alterations can be loss-of-function mutations (e.g., mutations resulting in reduced or eliminated protein function, including deletions) or gain-of-function mutations (e.g., mutations resulting in increased gene function, including overexpression and gene duplications). For example, a cell containing alterations in two of the genes of module M1 can contain loss-of-function mutations in both genes; can contain gain-of-function mutations in both genes; or can contain a loss-of-function mutation in the first gene and a gain-of-function mutation in the second gene. In some embodiments, at least one of the alterations is a loss-of-function alteration. In some embodiments, at least one of the alterations is a gain-of-function alteration.

[0399] In some embodiments, the genetically modified isolated cells are dendritic cells, macrophages, T cells, TILs, or NK cells. In some embodiments, the genetically modified isolated cells are for use in cell therapies described above, such as dendritic cell therapy, macrophage cell therapy, ACT, TIL therapy, engineered TCR therapy, CAR-T therapy, CAR-Treg therapy, monocyte or myeloid cell therapy, NK cell therapy, or therapies for use in regenerative medicine (e.g., Müller glia cell therapy or retinal ganglion cell (RGC) therapy). In some embodiments, the cell therapy is for treating cancer, inflammatory disease, or autoimmune disease.

[0400] IX. Pharmaceutical Compositions, Formulations, and Kits Any of the modulators or agents described herein can be used in pharmaceutical compositions and formulations. Pharmaceutical compositions and formulations of modulators or agents can be prepared in the form of lyophilized formulations or aqueous solutions by mixing one, two, three, or more of the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to, buffers such as phosphate, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (about 10 residues) soluble ... Examples of suitable pharmaceutically acceptable carriers include polypeptides (<1000 bases); 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 dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include intercalating drug dispersants, such as soluble neutral active hyaluronidase glycoproteins (sHASEGPs), e.g., human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.).Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in U.S. Patent Application Publication Nos. 2005 / 0260186 and 2006 / 0104968. In one embodiment, the sHASEGP is combined with one or more additional glycosaminoglycanases, such as chondroitinases.

[0401] The formulation herein may contain two or more active ingredients as needed for the specific indication to be treated, preferably those with complementary activities that do not adversely affect each other.For example, it may be desirable to further provide an additional therapeutic agent.Such active ingredients are suitably present in a combined amount that is effective for the intended purpose.

[0402] The active ingredient may be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0403] Sustained-release preparations may also be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the drug or modulator, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Preparations used for in vivo administration are generally sterile. Sterility can be easily achieved, for example, by filtration through sterile filtration membranes.

[0404] In some cases where the kit contains two or more agents or modulators, the agents or modulators are in the same container or separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. The containers can be formed from a variety of materials, such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloys (such as stainless steel or Hastelloy). In some cases, the container holds the formulation, and a label on or associated with the container can indicate instructions for use. The article of manufacture or kit can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts containing instructions for use. In some cases, the article of manufacture further includes one or more of the additional agents. Suitable containers for one or more include, for example, bottles, vials, bags, and syringes.

[0405] Any of the agents or modulators described herein may be included in an article of manufacture or kit, which may include instructions for administering the agent or modulator to a subject according to any of the methods described herein.

[0406] In some aspects, the disclosure features a kit including a modulator of the interaction between (a) one, two, or all three of Ldb2, Rnf165, and Traf2 and (b) CCR7 for treating an individual with cancer, an inflammatory disease, or an autoimmune disease by the methods provided herein in Section V. In some aspects, the kit includes a package insert containing instructions for administering the modulator to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0407] In some aspects, the disclosure features a kit that includes (a) an agent that decreases the expression and / or activity of Cebpb; (b) an agent that decreases the expression and / or activity of Traf2; and / or (c) an agent that increases the expression and / or activity of Dido1 for treating an individual with cancer, an inflammatory disease, or an autoimmune disease according to the methods provided in Section VI herein. In some aspects, the kit includes a package insert containing instructions for administering the agent to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0408] In some aspects, the disclosure features a kit that includes (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 for treating an individual with an inflammatory or autoimmune disease according to the methods provided in Section VI herein. In some aspects, the kit includes a package insert containing instructions for administering the agent to an individual with an inflammatory or autoimmune disease.

[0409] In some aspects, the disclosure features a kit including a modulator of the interaction between (a) Fbxw11 and (b) Nfkb1 or Nfkb2 for treating an individual with cancer, an inflammatory disease, or an autoimmune disease according to the methods provided in Section VII herein. In some aspects, the kit includes a package insert including instructions for administering the modulator to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0410] In some aspects, the disclosure features a kit including a cell therapy comprising cells comprising alterations in at least two of the genes within one or more of the cofunctional gene modules provided in Section VIII herein for treating an individual with cancer, an inflammatory disease, or an autoimmune disease according to the methods provided in Section VII herein. In some aspects, the kit includes a package insert including instructions for administering the agent to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0411] In some aspects, the disclosure features a kit including a cell therapy comprising cells comprising alterations in at least two of the genes within one or more of the following gene sets provided in Section VIII herein for treating an individual with cancer, an inflammatory disease, or an autoimmune disease according to the methods provided in Section VIII herein: In some aspects, the kit includes a package insert including instructions for administering the agent to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0412] In some aspects, the disclosure features a kit including 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 treating an individual with cancer, an inflammatory disease, or an autoimmune disease according to the methods provided in Section III(C) herein. In some aspects, the kit includes a package insert containing instructions for administering the modulator to an individual with cancer, an inflammatory disease, or an autoimmune disease.

[0413] In some aspects, the disclosure features a kit comprising a modulator of a gene in Table 1 or Table 2 for treating an individual having a disease or disorder associated with APCs and / or inflammation according to the methods provided in Section IV herein. In some aspects, the disclosure features a kit comprising a modulator of a gene in Table 1 for treating an individual having a disease or disorder associated with APCs and / or inflammation according to the methods provided in Section IV herein. In some aspects, the disclosure features a kit comprising a modulator of a gene in Table 2 for treating an individual having a disease or disorder associated with APCs and / or inflammation according to the methods provided in Section IV herein. In some aspects, the kit includes a package insert containing instructions for administering the modulator to an individual having a disease or disorder associated with APCs and / or inflammation.

[0414] All patents, patent publications and literature cited herein are hereby incorporated by reference in their entirety. [Example]

[0415] X. Example Example 1. Systematic screening of E3 ligases in immune dendritic cells This example describes a study characterizing a large gene family, E3 ligases, and their interacting partners in the cellular response of primary immune cells to inflammatory signals. The power of systematic Perturb-Seq to link different members of a gene family as regulators into distinct co-functional modules is demonstrated, along with their impact on the distribution of individual genes, co-regulated gene programs, and cellular states in a mixed population of related cell types. These examples also demonstrate how the modular structure of regulatory networks revealed by Perturb-Seq enables the study and prediction of the relationship of in vitro perturbations in model systems to the effects of gene interactions and mechanisms underlying disease risk in humans.

[0416] Since no human DC lines exist and patient-derived material limits the scale and reach of genetic perturbations, this study screened primary mouse cells and then linked these signals to human genetic signals to prioritize regulators that may also play a major role in human health and disease.

[0417] A. Introduction Despite systematic efforts in genetics and genomics, knowledge of the functions of many genes, especially those from large gene families, remains limited. While general molecular functions can be inferred from sequence characteristics, the specific mechanisms, biological processes, cellular contexts, and physiological effects of individual genes, as well as their combinations, often remain partially or completely unknown. Several approaches can help decipher individual gene function, including genome-wide association studies (GWAS), which link causative genetic variants to quantitative traits (1000 Genomes Project Consortium, Nature. 526:68-74, 2015); forward genetic screens, including cell viability, imaging, or molecular profiles, followed by phenotypic assessment (Bock et al., Nat. Rev. Methods Primer, 2:1-23, 2022); and guilt-by-association approaches, which rely on similarities in molecular patterns between a gene of interest and other genes. Despite their power and usefulness, each of these approaches has certain limitations. Genetic association studies are often limited by small effect sizes associated with common variants in human populations (Uffelmann et al., Nat. Rev. Methods Primer, 1;1-21, 2021); correlational approaches provide suggestive but not causal associations; forward genetic screens typically require pre-specifying phenotypes of interest, such as cell viability (Tsherniak et al., Cell, 170:564-576e.6, 2017) or cellular markers (Parnas et al., Cell, 162:675-686, 2015; Shifrut et al., Cell, 175:1958-1971e15, 2018). Ultimately, all approaches have difficulty deciphering genetic interactions due to limited power or experimental scale for testing exponentially large numbers of combinations.

[0418] Large protein families such as E3 ubiquitin ligases ("E3s") are a key example of this difficulty: the human genome encodes >600 different E3s responsible for catalyzing the ligation of ubiquitin (Ub) to substrates in nearly every biochemical pathway (Zhou et al., Nucleic Acids Res, 46:D447-D453, 2018), including many immune functions (Park et al., Adv. Immunol., 124:17-66, 2014). GWAS have linked variants in E3 ligase genes to many diseases, including inflammatory and autoimmune diseases (Kattah et al., J. Mol. Biol., 429:3471-3485, 2017; Senft et al., Nat. Rev. Cancer, 18:69-88, 2018), but characterizing their specific cellular roles remains challenging, as does determining their interrelationships. In particular, dendritic cells (DCs) play a key role in initiating immune responses, including multiple inflammatory and autoimmune diseases (Greb et al., Nat. Rev. Dis. Primer, 2:1-17, 2016; Lee et al., Science, 343:1246980, 2014). Inherited variants of multiple genes in DCs cont...

Claims

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

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

3. 2. The method of claim 1, wherein 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.

4. A method for increasing the expression of chemokine receptor type 7 (CCR7) in antigen-presenting cells (APCs), comprising contacting the APCs with an effective amount of an agent that decreases 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).

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

8. A method for increasing APC migration to tumors and / or lymph nodes in an individual, 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. 10. The method of claim 9, wherein migration of APCs to tumors and / or lymph nodes in an individual is increased by at least 10% compared to migration in the absence of the agent.

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

12. The method of claim 11, wherein the glial cells are microglial cells, 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, comprising administering to the individual an effective amount of an agent that decreases 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. 15. The method of claim 14, wherein T cell homing to the tumor in the individual is increased by at least 10% compared to T cell homing in the absence of the agent.

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

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

19. 19. The method of any one of claims 2 to 18, wherein the agent is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid.

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

21. The antigen-binding fragment may be bis-Fab, Fv, Fab, Fab'-SH, F(ab') ２ 20. The method of claim 19, wherein the antibody is a diabody, a linear antibody, an scFv, an scFab, a VH domain, or a VHH domain.

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

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

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

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

26. Akt1, Ankfy1, Apc, Arpc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, Chd4, Crebbp, Cul2, Dars, Dcaf10, Dcaf4, Eif3f, Eif3i, Ep300, Fbxl13, Fbxo28, Fbxo3, Fbx w9, Gm13416, Gnb1, Gnb2, Grb10, Klhl24, Klhl7, Kmt2c, Kmt2d, Mapk14, Med8, Mlst8, Mtor, Nosip, Paf1, Pik3r4, Pparg, Ppp2r2a, Ppp2r2d, Preb, Rbbp4, Rbb 26. The method of any one of claims 1 to 25, further comprising administering to the individual or contacting the APC with one or more agents that modulate expression of one or more of: p5, Rheb, Rictor, Rnf10, Rnf113a1, Rnf135, ​​Rnf216, Rptor, Scap, Sec13, Sec31a, Smad2, Syvn1, Taf51, Traf2, Traf3, Traf7, Trim24, Trp53, Ube2e1, Ube2e3, Ube3c, Ufm1, Wdfy3, Wdr1, Wdr82, Whsc1, and Zbtb11.

27. 27. A kit comprising a modulator of the interaction between (a) one, two, or all three of Ldb2, Rnf165, and Traf2 and (b) CCR7 for treating 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. 28. The kit of claim 27, comprising a package insert containing instructions for administering the modulator to an individual with cancer, an inflammatory disease, or an autoimmune disease.

29. 1. A method of 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, comprising: (i) determining the expression level of one or more of Ldb2, Rnf165, and Traf2 in a biological sample obtained from the individual at a time point after administration of the modulator; and (ii) comparing the expression level of one or more genes in the biological sample with a reference level, thereby monitoring the response in the individual to treatment with the modulator. A method comprising:

30. 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 administration of the modulator; (ii) the expression level of the one or more genes in a reference population; (iii) a pre-assigned 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 an earlier time point after administration of the modulator.

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

32. 31. The method of claim 29 or 30, wherein the individual has an inflammatory disease or an autoimmune disease, and the expression level of one or more genes is decreased in a biological sample obtained from the individual compared to a reference level, and the method further comprises 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 one, two, or all three of Ldb2, Rnf165, and Traf2.

33. 1. A method for treating cancer, an inflammatory disease, an autoimmune disease, or an infectious disease in an individual, comprising administering to an individual an effective amount of: (a) an agent that decreases the expression and / or activity of CCAAT / enhancer-binding protein beta (Cebpb); (b) an agent that decreases 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-Inducer-Obliterator 1 (Dido1) to an individual.

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

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

36. 1. A method for treating an inflammatory, autoimmune, or infectious disease in an individual, comprising administering to an individual an effective amount of: (a) an agent that increases the expression and / or activity of CCAAT / enhancer-binding protein beta (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-Inducer-Obliterator 1 (Dido1) to an individual.

37. 1. A method for increasing the proportion of migratory dendritic cells (mDCs) in an individual, comprising administering to an individual an effective amount of: (a) an agent that decreases the expression and / or activity of CCAAT / enhancer-binding protein beta (Cebpb); (b) an agent that decreases 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-Inducer-Obliterator 1 (Dido1) to an individual.

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

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

40. 1. A method for increasing anti-tumor immunity in an individual, comprising administering to an individual an effective amount of: (a) an agent that decreases the expression and / or activity of CCAAT / enhancer-binding protein beta (Cebpb); (b) an agent that decreases 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-Inducer-Obliterator 1 (Dido1) to an individual.

41. 41. The method of claim 40, wherein anti-tumor immunity in the individual is increased by at least 10% compared to anti-tumor immunity in the absence of the agent.

42. 1. A method for reducing the proportion of migratory dendritic cells (mDCs) in an individual, comprising administering to an individual an effective amount of: (a) an agent that increases the expression and / or activity of CCAAT / enhancer-binding protein beta (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 death-inducer-obliterator 1 (Dido1) expression and / or activity to an individual.

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

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

45. 1. A method for reducing autoimmune activity in an individual comprising administering to an individual an effective amount of: (a) an agent that increases the expression and / or activity of CCAAT / enhancer-binding protein beta (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 death-inducer-obliterator 1 (Dido1) expression and / or activity to an individual.

46. 46. ​​The method of claim 45, wherein autoimmune activity in the individual is reduced by at least 10% compared to anti-tumor immunity in the absence of the agent.

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

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

49. 49. The method of any one of claims 33 to 48, wherein the agent is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid.

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

51. The antigen-binding fragment may be bis-Fab, Fv, Fab, Fab'-SH, F(ab') ２ , a diabody, a linear antibody, scFv, scFab, a VH domain, or a VHH domain.

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

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

54. For individuals: (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, Nsmaf, Ogt, Pa2g4, Pcif1, Ppp1r11, Prc1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah2, Taf3, Tdpoz2, Tmem183a, Tnfsf11, Traddd, Traf3ip2, Trim35, Trim7, Tssc1, Ttc3, Ube2n, Ufl1, Unkl, Upf1, Vdr, Wdhhd1, 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, 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 54. The method of any one of claims 33 to 53, further comprising administering one or more agents that modulate expression of one or more of:

55. 55. A method for treating an individual with cancer, an inflammatory disease, or an autoimmune disease, according to any one of claims 33 and 47 to 54, (a) an agent that decreases the expression and / or activity of Cebpb; (b) an agent that decreases the expression and / or activity of Traf2; and / or (c) an agent that increases the expression and / or activity of Dido1 Kit including:

56. 56. The kit of claim 55, comprising a package insert containing instructions for administering the agent to an individual with cancer, an inflammatory disease, or an autoimmune disease.

57. 55. For treating an individual with an inflammatory or autoimmune disease by the method of any one of claims 34 and 47 to 54, (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 reduces the expression and / or activity of Dido1 Kit including:

58. 58. The kit of claim 57, comprising a package insert containing instructions for administering the agent to an individual with an inflammatory or autoimmune disease.

59. (a) an agent that decreases the expression and / or activity of Cebpb; (b) an agent that decreases the expression and / or activity of Traf2; and / or (c) an agent that increases the expression and / or activity of Dido1 1. A method for monitoring the response of an individual with cancer, an inflammatory disease, an autoimmune disease, or an infectious disease to treatment with (i) determining the expression level of one or more of Cebpb, Traf2, and Dido1 in a biological sample obtained from the individual at a time point after administration of the agent; and (ii) comparing the expression level of one or more genes in the biological sample with a reference level, thereby monitoring the response in the individual to treatment with the drug. A method comprising:

60. (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 reduces the expression and / or activity of Dido1 1. A method for monitoring the response of an individual with an inflammatory, autoimmune, or infectious disease to treatment with (i) determining the expression level of one or more of Cebpb, Traf2, and Dido1 in a biological sample obtained from the individual at a time point after administration of the agent; and (ii) comparing the expression level of one or more genes in the biological sample with a reference level, thereby monitoring the response in the individual to treatment with the drug. A method comprising:

61. 61. The method of claim 59 or 60, wherein 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 the individual prior to administration of the agent; (ii) the expression level of one or more genes in a reference population; (iii) a pre-assigned expression level for the one or more genes; or (iv) the expression level of one or more genes in a biological sample obtained from the individual at an earlier time point after administration of the agent.

62. (a) the expression and / or activity of Cebpb is increased in a biological sample obtained from the individual compared to a baseline level; (b) Traf2 expression and / or activity is increased in a biological sample obtained from the individual compared to baseline levels; and / or (c) the expression and / or activity of Dido1 is decreased in a biological sample obtained from the individual compared to baseline levels; 62. The method of claim 59 or 61, The method further comprises administering to the individual one or more additional doses of an agent that 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.

63. (a) the expression and / or activity of Cebpb is decreased in a biological sample obtained from the individual compared to baseline levels; (b) the expression and / or activity of Traf2 is decreased in a biological sample obtained from the individual relative to baseline levels; and / or (c) the expression and / or activity of Dido1 is increased in a biological sample obtained from the individual compared to baseline levels; 62. The method of claim 60 or 61, The method further comprises administering to the individual one or more additional doses of an agent that 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 cancer, an inflammatory disease, or an autoimmune disease in an individual, comprising administering to the individual an effective amount of a modulator of the interaction between (a) F-box and WD repeat domain containing 11 (Fbxw11) and (b) nuclear factor kappa B subunit 1 (Nfkb1) or nuclear factor kappa B subunit 2 (Nfkb2).

65. 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. 65. The method of claim 64, wherein the individual has an inflammatory or autoimmune disease and the modulator is an agent that decreases the expression and / or activity of Fbxw11.

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

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

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

70. A method according to any one of claims 67 to 69, wherein the level of Nfkb1 and / or Nfkb2 in the active form is increased by at least 10% compared to the level in the absence of the drug.

71. A method for reducing the processing of Nfkb1 and / or Nfkb2 into their active forms, comprising contacting a cell capable of expressing Fbxw11 with an agent that reduces the expression and / or activity of Fbxw11.

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

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

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

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

76. 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, comprising administering to the individual an effective amount of an agent that reduces the expression and / or activity of Fbxw11.

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

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

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

81. 81. The method of any one of claims 65 to 80, wherein the agent is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid.

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

83. The antigen-binding fragment may be bis-Fab, Fv, Fab, Fab'-SH, F(ab') ２ , a diabody, a linear antibody, scFv, scFab, a VH domain, or a VHH domain.

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

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

86. For individuals: (a) Acaca, Ambra1, Amfr, Arih1, Cbll1, Cfap57, Cnot4, Cyld, Dcaf7, Det1, Dpf2, Eed, Efcab8, Egr2, Fasn, Fbxw7, Fo xo3, Gsk3b, Hectd3, Hira, Icos, Ifnar1, Ikbke, Ints12, Junb, Kat6a, Kctd10, Kctd13, Kctd21, Kctd5, Klhl30, Klhl 6, 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 85. The method of any one of claims 64-66, 68-70, and 72-84, further comprising administering one or more agents that modulate expression of one or more of:

87. A kit comprising a modulator of the interaction between (a) Fbxw11 and (b) Nfkb1 or Nfkb2 for treating an individual with cancer, an inflammatory disease, or an autoimmune disease by a method described in any one of claims 64 to 66 and 79 to 86.

88. 88. The kit of claim 87, comprising a package insert containing instructions for administering the modulator to an individual with cancer, an inflammatory disease, or an autoimmune disease.

89. 1. A method of 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, comprising: (i) determining the expression level of the activated form of one or both of Nfkb1 and Nfkb2 in a biological sample obtained from the individual at a time point after administration of the modulator; and (ii) comparing the expression level of activated forms of one or both of Nfkb1 and Nfkb2 in the biological sample with a reference level, thereby monitoring the response in the individual to treatment with the modulator. A method comprising:

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

91. The method of claim 89 or 90, wherein the individual has cancer and the expression level of activated forms of one or both of Nfkb1 and Nfkb2 is decreased in a biological sample obtained from the individual compared to a reference level, and the method further comprises 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.

92. The method of claim 89 or 90, wherein the individual has an inflammatory disease or an autoimmune disease, and the expression level of activated forms of one or both of Nfkb1 and Nfkb2 is increased in a biological sample obtained from the individual compared to a reference level, and the method further comprises 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.

93. 1. A method for treating cancer, an inflammatory disease, or an autoimmune disease in an individual, comprising administering to an individual a co-functional gene module comprising: (a) Aamp, Bop1, Cirh1a, Dcaf13, Grb2, Myc, Nle1, Nol10, Pak1ip1, Ptpn11, module M1, including Rack1, Raf1, Rrp9, Taf5, Tbl3, Uhrf1, Utp15, Utp18, Vprbp, Wdr3, Wdr36, Wdr43, Wdr5, Wdr74, and Wdr75; Module M2 comprising 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, Gem in5, Gm10697, Gm9117, Gtf2h2, Gtf3c1, Hdac4, Hectd1, Ift122, Ikbkg, Ing2, Jun, Katnb1, Kbtbd13, Kdm2a, Klhl23, Klhl3, Kmt2b, LOC100861784, Lrr1, Lrr c41, Map3k7, Mdm4, Mib1, Mkrn1, Mnat1, Naca, Nsmaf, Ogt, Pa2g4, P cif1, Ppp1r11, Pr c1, Ring1, Rnf128, Rnf20, Rnf225, Rnf40, Siah1a, Siah2, Taf3, Tdpoz2, Tm em183a, Tnfsf11, Trad d, Traf3ip2, Trim35, Trim7, Tssc1, Ttc3, Ube2n, Ufl1, Unkl, Upf1, Vdr, Wdh d1, Wdr48, Wdr95, Wwp1, Ybx1, Zbtb14, Zbtb49, Zbtb7a, and Zmiz1; (c) Akt1, Ankfy1, Apc, Arpc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, 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, Pik3r 4, module M3 containing 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 contains Cdc40, Ddx41, Plrg1, Ppil2, Ppwd1, Prpf19, Prpf4, Sart1, Smu1, Snrnp40, and Wdr70; (e) 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, Lztr module M5, including 1, 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) Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fbxw11, Fus, Gm9840, Hif1 a, Huwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, Ranbp2, Rbbp6, Rbck1, R Module M6 includes bx1, 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. administering to the individual an effective amount of a cell therapy comprising cells comprising alterations in at least two of the genes within one or more of:

94. 1. A method for treating cancer, an inflammatory disease, or an autoimmune disease in an individual, comprising administering to an individual a set of genes comprising: Gene set 1 containing 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, 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, Rps3a1, Rps4x, Rps5, Rps6, Rps7, Rps8, Rps9, Rpsa, Rptor, Sgk1, Ssr4, Tab1, Taf5, Tpt1, Uhrf1, Uqcrh, Utp15, Wdr3, Wdr36, Wdr43, Wdr5, and Zbtb25; Gene set 2 comprising 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, Cxcl3, Cyb5a, Dap, Dars, Dck, Ddb1, Ddit3, Egr2, Eif3f, Eif3i, Ep300, Esd, Fbx15, Fbxw11, Gbe1, Gclm, Gdap10, Gm9840, Gss, Gstm1, H3f3b, Hmox1, Hvcn1, Il1f9, Inhba, Keap1, Lipa, Lmo4, Map3k7, Mcl1, Mcoln2, Met, Mgst2, Mmp12, Mmp19, Mmp8, Mylip, Nampt, Nedd8, Nf1, Npy, Nrp1, Nup43, Nupr1, Paf1, Pf4, Pgd, Phlda1, Pla2g7, Plet1, Ppfibp2, Prdx1, Prdx6, Preb, Prkcb, Proc, Ptgr1, Ptpn1, Raf1, Rbx1, RhoB, Rnase1, Rnf128, Runx2, Sdc4, Sec13, Seh1l, Skp1a, Slc43a2, Slc48a1, Slc7a11, Slpi, Smad2, Srxn1, Taldo1, Tarm1, Thbs1, Tlr2, Tlr4, Tma16, Tpm4, Traf2, Traf5, Traf6, Trip12, Tubb2a, Txnrd1, Ube2d3, Ube2n, Ubr5, Uchl1, Upf1, Wdr43, Wdr61, Zbtb17, and Zyx; (c) Acp5, Ankfy1, Arpc1b, Atp6v0d2, Bptf, Brap, C5ar1, Ccdc88a, Cd14, Cd36, Cd63, Cebpb, Ch d4, Clec4d, Clec5a, Cpd, Creg1, Ctsb, Ctsz, Cul3, Ddhd1, Dnmt3a, Egr2, Emb, F630028O10Rik, Fabp5, Fam46c, Fbxo42, Fcgr2b, Fn1, Foxo3, Fpr1, Ftl1, Gadd45a, Glrx, Gpnmb, Gpr84, Huwe1, Icam1, Id1, Il1f9, Kctd10, Keap1, Klhl6, Lcn2, Lgals1, Lgals3, Lgmn, Lipa, Lpcat2, Ly6c2, M arch6, Metrnl, Mgll, Mt1, Mtor, Myof, Naaa, Naca, Nf1, Paf1, Phlda1, Pid1, Pik3r4, Pld3, Ple t1, Plk2, Pou2f2, Pparg, Prdx5, Psap, Ptpn11, Rab3il1, Rela, Rfwd2, Rnase2a, S100a1, S100a 11, gene set 3 including S100a8, Saa3, Sdc3, Serpinb2, Slamf7, Snx18, Sod2, Spata13, Stap1, Strap, Tab1, Tceb2, Tgfbi, Thbs1, Trem1, Upf1, Upp1, Vat1, Wdfy3, Wfdc21, 2010005H15Rik, and Zbtb25; Gene set 4 comprising AC160336.1, Actb, Actg1, Ankfy1, Arhgdib, Bptf, Brap, Bri3, Ccr2, Ccr5, Cd274, Cdkna, Cfl1, Chd4, Clec4a2, Copa, Coro1a, Cotl1, Crip1, Cul1, Cul3, Dars, Ddhhd1, Ddit3, Ear2, Eif3f, Eif3i, Ep300, Fbxw11, Flna, Gbp2, Gbp5, Grb2, Gtf3c1, H2-D1, H2-K1, Huwe1, Ifi27l2a, Il1rn, Keap1, Klk1b1, Lcp1, Lgals1, Lpl, Lrr1, Lsp1, Malat1, Marks11, Med8, Mgl1, Mndal, Mtor, Naca, Nedd8, Nf1, Paf1, Pfn1, Pik3r4, Pten, Ptma, Ptpn11, Rack1, RelA, Rnf20, Sdc4, Skp1a, Taf3, Taf5, Tlr4, Tmsb4x, Ubb, Ube2i, Upf1, Vhl, Wdfy3, Wdr43, Wdr82, and Wfdc17; Gene set 5 comprising AA467197, AW112010, Abcg1, Acod1, Bcl2a1b, Bcl2a1d, Cav1, Ccl17, Ccl3, Ccl4, Cd14, Cd200r1, Cd300lf, Cdkna, Cebpb, Cflar, Chd4, Clec4e, Clc4, Copa, Cpd, Cpeb4, Cul1, Cul3, Cxcl1, Cxcl2, Cxcl3, Ehd1, Ep300, Fam102b, Fam20c, Fbxw11, Gda, Gpr84, Hist1h1c, Hivep3, Ikbke, Ikbkg, Il12b, Il1a, Il1b, Il6, Ing3, Inhba, Kctd21, Klf4, Laptm5, Mafb, Malat1, Malt1, Marks, Marks11, Marco, Met, Mtpn, Nabp1, Nedd8, Nfkb1, Nfkbiz, Nlrp3, Nrp2, Nup62, Ogt, Paf1, Plek, Plrg1, Ppfia3, Prpf19, Ptgs2, Ptx3, Rassf4, Rbx1, RelA, Rfwd2, Rnf31, Serpinb2, Sh3bp5, Skp1a, Slc7a11, Slc7a2, Slco3a1, Slfn2, Smad2, Smu1, Socs6, Sod2, Spop, Stub1, Tank, Tbk1, Tceb3, Tlr4, Tnf, Tnfaip3, Tnfsf15, Traddd, Traf6, Trip12, Txnip, Ube2d3, Ube2i, Ube2n, Wdr82, Zbtb17, and Zc3h12c; (f) AA467197, Ahr, Akt1, Ankfy1, Axl, Bhlhe40, Bhlhe41, Btg1, Ccl17, Ccl22, Ccr2, Cd40, C d52, Cd74, Cebpb, Chd4, Clec4e, Clec4n, Clic4, Cst3, Cstf1, Ctsb, Ctsd, Cxcl16, Dcstamp, E gr2, Etv3, Fabp4, Fabp5, Fam20c, Fbxw7, Fbxw9, Foxo3, Fpr1, Fth1, Ftl1, Gbp2, Gbp5, Gm2a, G nb1, Gnb2, Grb2, Grk3, Gsk3b, H2-Aa, H2-Ab1, Hmox1, Igf1, Il4i1, Irf4, Itgax, Jak2, Jund, K cmf1, Klhl6, Kmt2d, Lgals1, Lyz2, March6, Mgl2, Mmp12, Mtor, Myc, Ndufa4, Nectin2, Nf1, N fkb1, Pfkp, Pid1, Pik3r4, Plet1, Pmp22, Pten, Ptpn1, Ptpn11, Rheb, Rilpl2, Rptor, S100a8, gene set 6, including 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) 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, Inhba, Keap1, Km gene set 7, including t2d, 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; Gene set 8 comprising Aamp, Acsl1, Ambra1, Arf4, Arih2, Atf4, Bop1, C1qb, Calr, Canx, Ccng1, Cdkna1, Chd4, Cirh1a, Clec2d, Copa, Copb2, Cope, Cpd, Cts, Cul3, Dad1, Dap, Dcaf13, Ddit3, Ddx41, Dstn, Eif3f, Eif3i, Erp29, Fbxw7, Fth1, Ftl1, Gm9840, Grb2, Gtf3c1, Herpud1, Hif1a, Hnrnpa3, Hsp90b1, Hspa5, Ift20, Keap1, Kmt2d, Krtcap2, Lgals3, Lrr1, Lyz2, Manf, Map3k7, Mthfd2, Mtor, Myc, Naca, Nedd8, Nf1, Nol10, Ostc, P4hb, Pdia3, Pdia4, Pdia6, Phgdh, Plrg1, Preb, Prpf19, Pten, Ptpn1, Rack1, Rbx1, Rel, Rpl22l1, Rpn1, Rps19, Rrp9, Sdf2l1, Sec11c, Sec13, Sec22b, Sec31a, Sec61b, Sec61g, Selenos, Serf2, Serp1, Sf3b5, Spcs2, Ssr3, Surf4, Syn1, Tceal9, Tceb1, Tceb2, Tim13, Tpt1, Tram1, Trp53, Ube2f, Ufm1, Uqcrq, Utp15, Vcp, Vhl, Vprbp, Wdr36, Wdr43, Wdr5, Wdr74, Wdr75, and Xbp1; (i)Gene set 9 comprising Acod1, Adam8, Atp5g3, Brapp, C3ar1, Ccl2, Ccl3, Ccl4, Ccl7, Ccnd1, Cd300ld, Cd63, Ch25h, Chd4, Chil3, Crip1, Ctsb, Ctsl, Cul1, Cul3, Cxcl1, Cyp51, Det1, Ear2, Egr2, F10, Fbxo42, Fbxw11, 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, Ly6c2, Lztri, Maf, March6, Mcemp1, Mmp12, Mmp13, Mmp8, Msr1, Mtor, Naaa, Naca, Nf1, Nfkbiz, Npc2, Npy, Paf1, Pdpn, Pf4, Plet1, Pparg, Prkcd, Pten, Ptgs2, Ptpn1, Ptpn11, Ptprc, Ptx3, Rbbp5, RelA, Rfwd2, 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; Gene set 10 comprising 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, Lyz2, March6, Mif, Mt1, Mt2, mTor, Myc, Ndufv3, Nf1, Pdk1, Pfkl, Pgam1, Pgk1, Pgm2, Pkm, Prdx1, Prelid1, Ptpn1, Ptpn11, Rbpj, Rfwd2, Rilpl2, Rnase2a, Sacs, Scd2, Sdc3, Sdc4, Sec13, Slamf9, Slc16a3, Slc2a1, Slc7a2, Smu1, Socs3, Strap, Tarm1, Tceb1, Tceb2, Tgm2, Tlr4, Tpi1, Trf, Ube2f, Vhl, Vim, Wdr43, Wdr82, Wfdc17, and 2010005H15Rik; (k) 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, I l4i1, Inhba, Itgax, Itgb2, Kctd10, Klk1b11, Lpl, Maf, Marcks, Marcksl1, Med8, Met, Mmp 12, Ms4a6c, Ms4a7, Mt2, Mycbp2, Naca, Nedd8, Nfkbia, Phlda1, Plaur, Plrg1, Pparg, Ppf ibp2, Prpf19, Ptpn1, Rassf4, Rfwd2, Ring1, Rnase2a, Rpl12, Scimp, Sec13, Skp1a, Slc43 Gene set 11 including a2, Smu1, Sqstm1, Syk, Syvn1, Taf5l, Tceb2, Tmem176a, Tmem176b, Tnfaip2, Traf3, Ufm1, Upp1, Wdr5, Wdr70, Wdr82, Wfdc17, Wfdc21, 0610012G03Rik, Zbtb7a, and Zyx; (l) Ambra1, Aplp2, 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, Nupr gene set 12, including 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) Ankfy1, Anxa1, Anxa5, Aph1c, Brap, C3ar1, Ccnd2, Ccr1, Cd300lf, Cd38, Cd68, Cd9, Cdc27, Cdc40, Cebpb, Chd4, Chst11, Clec4e, Creb5, Cul1, Cul3, Cxcl3, Cyba, Dstn, Eif 3f, Eif3i, Emp1, Epha4, Fam102b, Fam46a, Fbxw11, Fn1, Foxo3, Ftl1, Furin, Gas7, Gdf1 5, Grb2, H2-K1, Huwe1, Icam1, Il7r, Inhba, Keap1, Klhdc4, Klk1b11, Lgals3, Lpl, Ly6c 2, Lyz2, March6, Mbnl1, Mmp14, Mmp8, Ms4a7, Naca, Neat1, Nf1, Nrp2, Plin2, Plk2, Plrg 1, Polr2l, Prdx1, Pten, Ptpn1, Rack1, Rasgef1b, Rasgrp1, Rela, Rnf20, Rnh1, Rpl22l1 , gene set 13 including 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) AC160336.1, Adgre1, Adgre4, Adgrl2, Anxa1, B2m, C1qb, C3, Car4, Ccdc88a, Ccl6, C d52, 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, M pc1, Ms4a6d, Msrb1, Mt1, Mt2, Nedd8, Nfe2l2, Nov, Npc2, Paf1, Pdzk1ip1, Phgdh, Pias1, Pla2g7, Plrg1, Ppic, Ppil2, Ppwd1, Prkcd, Prpf19, Ptges, Rab32, Rbx1, Rela, Rps20, S1 Gene set 14 includes 00a11, Sart1, Selenow, Smu1, St8sia4, Tab1, Taf5l, Tceb2, Tmem176a, Tmem176b, Tnip3, Traf2, Tyrobp, Ube2i, Uchl1, Wdr5, Wdr70, Wdr82, Zbtb25, and Zfp106; and (o) AC160336.1, Adgre1, Ahnak, Alcam, Aprt, Bcl2l11, Blvrb, Brap, Bub3, C1qb, C1qc , C3ar1, Cd300c2, Cd33, Cd68, Cdc40, Cebpb, Chchd2, Clec12a, Clec4n, Copa, Csf1r, Ct sz, Cul3, Cul5, Cyba, Ddx41, Dstn, Egr2, Ep300, F7, Fbxw7, Fcer1g, Fcgr2b, Gmfg, Gngt 2, Gpr84, Hsp90aa1, Huwe1, Igf1, Kat6a, Kctd12b, Kdm5c, Keap1, Kmt2d, Lst1, Mmp14, M peg1, Myc, Naca, P2ry14, Paf1, Pirb, Plrg1, Pou2f2, Pparg, Ppil2, Ppwd1, Prkcd, Prpf 19, Prpf4, Ptpn1, Ptpn18, Rack1, Rbbp5, Rnf20, Rnf40, Rnf7, Rps27l, Sat1, Serpinb2, Gene set 15 includes Smu1, Socs3, Spp1, Taf5, Tank, Tceb1, Tceb2, Tgm2, Tnfsf15, Traf2, Trem2, Tyrobp, Ufm1, Vcan, Wdr1, Wdr33, Wdr43, Wdr5, Wdr61, Wdr70, Wdr82, Wfdc21, and Ybx1. administering to the individual an effective amount of a cell therapy comprising cells comprising alterations in at least two of the genes within one or more of:

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

96. 96. A kit comprising a cell therapy comprising cells comprising alterations in at least two of the genes within one or more of the co-functional genetic modules of claim 93 for treating an individual having cancer, an inflammatory disease, or an autoimmune disease by the method of claim 93 or 95.

97. 96. A kit comprising reagents for modifying cells to contain alterations in at least two of the genes within one or more of the co-functional genetic modules of claim 93 for treating an individual with cancer, an inflammatory disease, or an autoimmune disease by the method of claim 93 or 95.

98. 98. The kit of claim 96 or 97, comprising a package insert containing instructions for administering the agent to an individual with cancer, an inflammatory disease, or an autoimmune disease.

99. 96. A kit comprising a cell therapy comprising cells comprising alterations in at least two of the genes within one or more of the sets of genes of claim 94 for treating an individual having cancer, an inflammatory disease, or an autoimmune disease by the method of claim 94 or 95.

100. 96. A kit comprising reagents for modifying cells to contain alterations in at least two of the genes within one or more of the gene sets of claim 94 for treating an individual with cancer, an inflammatory disease, or an autoimmune disease by the method of claim 94 or 95.

101. 101. The kit of claim 99 or 100, comprising a package insert containing instructions for administering the agent to an individual with cancer, an inflammatory disease, or an autoimmune disease.

102. The following cofunctional gene modules: (a) Aamp, Bop1, Cirh1a, Dcaf13, Grb2, Myc, Nle1, Nol10, Pak1ip1, Ptpn11, module M1, including Rack1, Raf1, Rrp9, Taf5, Tbl3, Uhrf1, Utp15, Utp18, Vprbp, Wdr3, Wdr36, Wdr43, Wdr5, Wdr74, and Wdr75; Module M2 containing 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, Traddd, Traf3ip2, Trim35, Trim7, Tssc1, Ttc3, Ube2n, Ufl1, Unkl, Upf1, Vdr, Wdh1, Wdr48, Wdr95, Wwp1, Ybx1, Zbtb14, Zbtb49, Zbtb7a, and Zmiz1; (c) Akt1, Ankfy1, Apc, Arpc1b, Birc2, Bmi1, Bub3, Cacybp, Cebpb, 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, Pik3r 4, module M3 containing 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 contains Cdc40, Ddx41, Plrg1, Ppil2, Ppwd1, Prpf19, Prpf4, Sart1, Smu1, Snrnp40, and Wdr70; (e) 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, Lztr module M5, including 1, 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) Ahctf1, Anapc11, Arih2, Arnt, Bcl6, Brap, Cbl, Cd28, Cstf1, Cul1, Cul3, Cul5, Dda1, Fbxo33, Fbxw11, Fus, Gm9840, Hif1 a, Huwe1, Ing3, Kcmf1, Kdm5c, Keap1, Maea, Mycbp2, Nbeal1, Nedd8, Nup43, Nup62, Phf8, Ptpn1, Rae1, Ranbp2, Rbbp6, Rbck1, R Module M6 includes bx1, 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. A genetically modified isolated cell comprising an alteration in at least two of the genes within one or more of:

103. The following gene sets: Gene set 1 containing Aamp, Actb, Alcam, Ambra1, Annex2, 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, 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, Rps3a1, Rps4x, Rps5, Rps6, Rps7, Rps8, Rps9, Rpsa, Rptor, Sgk1, Ssr4, Tab1, Taf5, Tpt1, Uhrf1, Uqcrh, Utp15, Wdr3, Wdr36, Wdr43, Wdr5, and Zbtb25; Gene set 2 comprising 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, Cxcl3, Cyb5a, Dap, Dars, Dck, Ddb1, Ddit3, Egr2, Eif3f, Eif3i, Ep300, Esd, Fbx15, Fbxw11, Gbe1, Gclm, Gdap10, Gm9840, Gss, Gstm1, H3f3b, Hmox1, Hvcn1, Il1f9, Inhba, Keap1, Lipa, Lmo4, Map3k7, Mcl1, Mcoln2, Met, Mgst2, Mmp12, Mmp19, Mmp8, Mylip, Nampt, Nedd8, Nf1, Npy, Nrp1, Nup43, Nupr1, Paf1, Pf4, Pgd, Phlda1, Pla2g7, Plet1, Ppfibp2, Prdx1, Prdx6, Preb, Prkcb, Proc, Ptgr1, Ptpn1, Raf1, Rbx1, RhoB, Rnase1, Rnf128, Runx2, Sdc4, Sec13, Seh1l, Skp1a, Slc43a2, Slc48a1, Slc7a11, Slpi, Smad2, Srxn1, Taldo1, Tarm1, Thbs1, Tlr2, Tlr4, Tma16, Tpm4, Traf2, Traf5, Traf6, Trip12, Tubb2a, Txnrd1, Ube2d3, Ube2n, Ubr5, Uchl1, Upf1, Wdr43, Wdr61, Zbtb17, and Zyx; (c) Acp5, Ankfy1, Arpc1b, Atp6v0d2, Bptf, Brap, C5ar1, Ccdc88a, Cd14, Cd36, Cd63, Cebpb, Ch d4, Clec4d, Clec5a, Cpd, Creg1, Ctsb, Ctsz, Cul3, Ddhd1, Dnmt3a, Egr2, Emb, F630028O10Rik, Fabp5, Fam46c, Fbxo42, Fcgr2b, Fn1, Foxo3, Fpr1, Ftl1, Gadd45a, Glrx, Gpnmb, Gpr84, Huwe1, Icam1, Id1, Il1f9, Kctd10, Keap1, Klhl6, Lcn2, Lgals1, Lgals3, Lgmn, Lipa, Lpcat2, Ly6c2, M arch6, Metrnl, Mgll, Mt1, Mtor, Myof, Naaa, Naca, Nf1, Paf1, Phlda1, Pid1, Pik3r4, Pld3, Ple t1, Plk2, Pou2f2, Pparg, Prdx5, Psap, Ptpn11, Rab3il1, Rela, Rfwd2, Rnase2a, S100a1, S100a 11, gene set 3 including S100a8, Saa3, Sdc3, Serpinb2, Slamf7, Snx18, Sod2, Spata13, Stap1, Strap, Tab1, Tceb2, Tgfbi, Thbs1, Trem1, Upf1, Upp1, Vat1, Wdfy3, Wfdc21, 2010005H15Rik, and Zbtb25; Gene set 4 comprising AC160336.1, Actb, Actg1, Ankfy1, Arhgdib, Bptf, Brap, Bri3, Ccr2, Ccr5, Cd274, Cdkna, Cfl1, Chd4, Clec4a2, Copa, Coro1a, Cotl1, Crip1, Cul1, Cul3, Dars, Dddh1, Ddit3, Ear2, Eif3f, Eif3i, Ep300, Fbxw11, Flna, Gbp2, Gbp5, Grb2, Gtf3c1, H2-D1, H2-K1, Huwe1, Ifi27l2a, Il1rn, Keap1, Klk1b1, Lcp1, Lgals1, Lpl, Lrr1, Lsp1, Malat1, Marks1, Med8, Mgl1, Mndal, Mtor, Naca, Nedd8, Nf1, Paf1, Pfn1, Pik3r4, Pten, Ptma, Ptpn11, Rack1, RelA, Rnf20, Sdc4, Skp1a, Taf3, Taf5, Tlr4, Tmsb4x, Ubb, Ube2i, Upf1, Vhl, Wdfy3, Wdr43, Wdr82, and Wfdc17; Gene set 5 comprising AA467197, AW112010, Abcg1, Acod1, Bcl2a1b, Bcl2a1d, Cav1, Ccl17, Ccl3, Ccl4, Cd14, Cd200r1, Cd300lf, Cdkna, Cebpb, Cflar, Chd4, Clec4e, Cltc4, Copa, Cpd, Cpeb4, Cul1, Cul3, Cxcl1, Cxcl2, Cxcl3, Ehd1, Ep300, Fam102b, Fam20c, Fbxw11, Gda, Gpr84, Hist1h1c, Hivep3, Ikbke, Ikbkg, Il12b, Il1a, Il1b, Il6, Ing3, Inhba, Kctd21, Klf4, Laptm5, Mafb, Malat1, Malt1, Marks, Marks11, Marco, Met, Mtpn, Nabp1, Nedd8, Nfkb1, Nfkbi, Nlrp3, Nrp2, Nup62, Ogt, Paf1, Plek, Plrg1, Ppfia3, Prpf19, Ptgs2, Ptx3, Rassf4, Rbx1, Rel, Rfwd2, Rnf31, Serpinb2, Sh3bp5, Skp1a, Slc7a11, Slc7a2, Slco3a1, Slfn2, Smad2, Smu1, Socs6, Sod2, Spop, Stub1, Tank, Tbk1, Tceb3, Tlr4, Tnf, Tnfaip3, Tnfsf15, Trad, Traf6, Trip12, Txnip, Ube2d3, Ube2i, Ube2n, Wdr82, Zbtb17, and Zc3h12c; (f) AA467197, Ahr, Akt1, Ankfy1, Axl, Bhlhe40, Bhlhe41, Btg1, Ccl17, Ccl22, Ccr2, Cd40, C d52, Cd74, Cebpb, Chd4, Clec4e, Clec4n, Clic4, Cst3, Cstf1, Ctsb, Ctsd, Cxcl16, Dcstamp, E gr2, Etv3, Fabp4, Fabp5, Fam20c, Fbxw7, Fbxw9, Foxo3, Fpr1, Fth1, Ftl1, Gbp2, Gbp5, Gm2a, G nb1, Gnb2, Grb2, Grk3, Gsk3b, H2-Aa, H2-Ab1, Hmox1, Igf1, Il4i1, Irf4, Itgax, Jak2, Jund, K cmf1, Klhl6, Kmt2d, Lgals1, Lyz2, March6, Mgl2, Mmp12, Mtor, Myc, Ndufa4, Nectin2, Nf1, N fkb1, Pfkp, Pid1, Pik3r4, Plet1, Pmp22, Pten, Ptpn1, Ptpn11, Rheb, Rilpl2, Rptor, S100a8, gene set 6, including 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) 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, Inhba, Keap1, Km gene set 7, including t2d, 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; Gene set 8 comprising Aamp, Acsl1, Ambra1, Arf4, Arih2, Atf4, Bop1, C1qb, Calr, Canx, Ccng1, Cdkna1, Chd4, Cirh1a, Clec2d, Copa, Copb2, Cope, Cpd, Cts, Cul3, Dad1, Dap, Dcaf13, Ddit3, Ddx41, Dstn, Eif3f, Eif3i, Erp29, Fbxw7, Fth1, Ftl1, Gm9840, Grb2, Gtf3c1, Herpud1, Hif1a, Hnrnpa3, Hsp90b1, Hspa5, Ift20, Keap1, Kmt2d, Krtcap2, Lgals3, Lrr1, Lyz2, Manf, Map3k7, Mthfd2, Mtor, Myc, Naca, Nedd8, Nf1, Nol10, Ostc, P4hb, Pdia3, Pdia4, Pdia6, Phgdh, Plrg1, Preb, Prpf19, Pten, Ptpn1, Rack1, Rbx1, Rel, Rpl22l1, Rpn1, Rps19, Rrp9, Sdf2l1, Sec11c, Sec13, Sec22b, Sec31a, Sec61b, Sec61g, Selenos, Serf2, Serp1, Sf3b5, Spcs2, Ssr3, Surf4, Syn1, Tceal9, Tceb1, Tceb2, Tim13, Tpt1, Tram1, Trp53, Ube2f, Ufm1, Uqcrq, Utp15, Vcp, Vhl, Vprbp, Wdr36, Wdr43, Wdr5, Wdr74, Wdr75, and Xbp1; (i)Gene set 9 comprising Acod1, Adam8, Atp5g3, Brapp, C3ar1, Ccl2, Ccl3, Ccl4, Ccl7, Ccnd1, Cd300ld, Cd63, Ch25h, Chd4, Chil3, Crip1, Ctsb, Ctsl, Cul1, Cul3, Cxcl1, Cyp51, Det1, Ear2, Egr2, F10, Fbxo42, Fbxw11, 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, Ly6c2, Lztri, Maf, March6, Mcemp1, Mmp12, Mmp13, Mmp8, Msr1, Mtor, Naaa, Naca, Nf1, Nfkbiz, Npc2, Npy, Paf1, Pdpn, Pf4, Plet1, Pparg, Prkcd, Pten, Ptgs2, Ptpn1, Ptpn11, Ptprc, Ptx3, Rbbp5, RelA, Rfwd2, 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; Gene set 10 comprising 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, Lyz2, March6, Mif, Mt1, Mt2, Mtor, Myc, Ndufv3, Nf1, Pdk1, Pfkl, Pgam1, Pgk1, Pgm2, Pkm, Prdx1, Prelid1, Ptpn1, Ptpn11, Rbpj, Rfwd2, Rilpl2, Rnase2a, Sacs, Scd2, Sdc3, Sdc4, Sec13, Slamf9, Slc16a3, Slc2a1, Slc7a2, Smu1, Socs3, Strap, Tarm1, Tceb1, Tceb2, Tgm2, Tlr4, Tpi1, Trf, Ube2f, Vhl, Vim, Wdr43, Wdr82, Wfdc17, and 2010005H15Rik; (k) 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, I l4i1, Inhba, Itgax, Itgb2, Kctd10, Klk1b11, Lpl, Maf, Marcks, Marcksl1, Med8, Met, Mmp 12, Ms4a6c, Ms4a7, Mt2, Mycbp2, Naca, Nedd8, Nfkbia, Phlda1, Plaur, Plrg1, Pparg, Ppf ibp2, Prpf19, Ptpn1, Rassf4, Rfwd2, Ring1, Rnase2a, Rpl12, Scimp, Sec13, Skp1a, Slc43 Gene set 11 including a2, Smu1, Sqstm1, Syk, Syvn1, Taf5l, Tceb2, Tmem176a, Tmem176b, Tnfaip2, Traf3, Ufm1, Upp1, Wdr5, Wdr70, Wdr82, Wfdc17, Wfdc21, 0610012G03Rik, Zbtb7a, and Zyx; (l) Ambra1, Aplp2, 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, Nupr gene set 12, including 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) Ankfy1, Anxa1, Anxa5, Aph1c, Brap, C3ar1, Ccnd2, Ccr1, Cd300lf, Cd38, Cd68, Cd9, Cdc27, Cdc40, Cebpb, Chd4, Chst11, Clec4e, Creb5, Cul1, Cul3, Cxcl3, Cyba, Dstn, Eif 3f, Eif3i, Emp1, Epha4, Fam102b, Fam46a, Fbxw11, Fn1, Foxo3, Ftl1, Furin, Gas7, Gdf1 5, Grb2, H2-K1, Huwe1, Icam1, Il7r, Inhba, Keap1, Klhdc4, Klk1b11, Lgals3, Lpl, Ly6c 2, Lyz2, March6, Mbnl1, Mmp14, Mmp8, Ms4a7, Naca, Neat1, Nf1, Nrp2, Plin2, Plk2, Plrg 1, Polr2l, Prdx1, Pten, Ptpn1, Rack1, Rasgef1b, Rasgrp1, Rela, Rnf20, Rnh1, Rpl22l1 , gene set 13 including 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) AC160336.1, Adgre1, Adgre4, Adgrl2, Anxa1, B2m, C1qb, C3, Car4, Ccdc88a, Ccl6, C d52, 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, M pc1, Ms4a6d, Msrb1, Mt1, Mt2, Nedd8, Nfe2l2, Nov, Npc2, Paf1, Pdzk1ip1, Phgdh, Pias1, Pla2g7, Plrg1, Ppic, Ppil2, Ppwd1, Prkcd, Prpf19, Ptges, Rab32, Rbx1, Rela, Rps20, S1 Gene set 14 includes 00a11, Sart1, Selenow, Smu1, St8sia4, Tab1, Taf5l, Tceb2, Tmem176a, Tmem176b, Tnip3, Traf2, Tyrobp, Ube2i, Uchl1, Wdr5, Wdr70, Wdr82, Zbtb25, and Zfp106; and (o) AC160336.1, Adgre1, Ahnak, Alcam, Aprt, Bcl2l11, Blvrb, Brap, Bub3, C1qb, C1qc , C3ar1, Cd300c2, Cd33, Cd68, Cdc40, Cebpb, Chchd2, Clec12a, Clec4n, Copa, Csf1r, Ct sz, Cul3, Cul5, Cyba, Ddx41, Dstn, Egr2, Ep300, F7, Fbxw7, Fcer1g, Fcgr2b, Gmfg, Gngt 2, Gpr84, Hsp90aa1, Huwe1, Igf1, Kat6a, Kctd12b, Kdm5c, Keap1, Kmt2d, Lst1, Mmp14, M peg1, Myc, Naca, P2ry14, Paf1, Pirb, Plrg1, Pou2f2, Pparg, Ppil2, Ppwd1, Prkcd, Prpf 19, Prpf4, Ptpn1, Ptpn18, Rack1, Rbbp5, Rnf20, Rnf40, Rnf7, Rps27l, Sat1, Serpinb2, Gene set 15 includes Smu1, Socs3, Spp1, Taf5, Tank, Tceb1, Tceb2, Tgm2, Tnfsf15, Traf2, Trem2, Tyrobp, Ufm1, Vcan, Wdr1, Wdr33, Wdr43, Wdr5, Wdr61, Wdr70, Wdr82, Wfdc21, and Ybx1. A genetically modified isolated cell comprising an alteration in at least two of the genes within one or more of:

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

105. 104. The method of any one of claims 93 to 95, the kit of any one of claims 97 to 101, or the genetically modified cell of claim 102 or 103, wherein at least one of the alterations is a gain-of-function alteration.

106. 104. The method of any one of claims 93 to 95, the kit of any one of claims 97 to 101, or the genetically modified cell of claim 102 or 103, wherein the genetically modified isolated cell comprises a loss-of-function alteration in one, two, or all three of Ldb2, Rnf165, and Traf2.

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

108. A method according to any one of claims 93 to 95, a kit according to any one of claims 97 to 101, or a genetically modified cell according to claim 102 or 103, wherein the genetically modified isolated cell comprises a gain-of-function alteration in CCR7.

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

110. 1. A method for identifying a modulator of the interaction between F-box and WD repeat domain containing 11 (Fbxw11) and nuclear factor kappa B subunit 1 (Nfkb1) or nuclear factor kappa B subunit 2 (Nfkb2), comprising: (a) providing a candidate modulator; (b) contacting Fbxw11 with Nfkb1 or Nfkb2 in the presence or absence of a candidate modulator under conditions that allow binding of Fbxw11 to Nfkb1 or Nfkb2; (c) measuring the binding of Fbxw11 to Nfkb1 or Nfkb2, wherein an increase or decrease in binding in the presence of the candidate modulator compared 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; and A method comprising:

111. 1. A method for identifying a modulator of a downstream activity of Fbxw11, comprising: (a) providing a candidate modulator; (b) contacting Fbxw11 with Nfkb1 or Nfkb2 in the presence or absence of a candidate modulator under conditions that allow binding of Fbxw11 to Nfkb1 or Nfkb2; (c) measuring downstream activity of Fbxw11, wherein a change in downstream activity in the presence of the candidate modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of Fbxw11; A method comprising:

112. 1. A method for identifying a modulator of a downstream activity of Nfkb1 or Nfkb2, comprising: (a) providing a candidate modulator; (b) contacting Nfkb1 or Nfkb2 with Fbxw11 in the presence or absence of a candidate modulator under conditions that allow binding of Nfkb1 or Nfkb2 to Fbxw11; (c) measuring downstream activity of Nfkb1 or Nfkb2, wherein a change in downstream activity in the presence of the candidate modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of Nfkb1 or Nfkb2; A method comprising:

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

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

115. 113. 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. 113. The method of claim 111 or 112, wherein the change in downstream activity is a decrease in the amount, intensity, or duration of the downstream activity.

117. 117. The method of any one of claims 110 to 116, wherein the modulator is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid.

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

119. The antigen-binding fragment may be bis-Fab, Fv, Fab, Fab'-SH, F(ab') ２ , a diabody, a linear antibody, scFv, scFab, a VH domain, or a VHH domain.

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

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

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

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

124. A method for treating cancer in an individual, 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.

125. A method for treating an inflammatory or autoimmune disease in an individual, 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. 1. A method for identifying a modulator of the interaction between 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); anaphase-promoting complex subunit 13 (Anapc13); Cullin 2 (Cul2); Cullin 5 (Cul5); HECT, UBA, and WWE domain-containing E3 ubiquitin protein ligase 1 (Huwe1); CREB-binding protein (Crebbp); S-phase kinase-associated protein 1 (Skp1a); developmentally down-regulated gene expressed in neural precursor cells 8 (Nedd8); Cullin 1 (Cul1); and WD repeat domain 5 (Wdr5), comprising: (a) providing a candidate modulator; (b) contacting Rfwd2 with a query protein in the presence or absence of a candidate modulator under conditions that allow binding of Rfwd2 to the query protein; (c) measuring binding of Rfwd2 to the query protein, wherein an increase or decrease in binding in the presence of the candidate modulator compared to binding in the absence of the candidate modulator identifies the candidate modulator as a modulator of the interaction between Rfwd2 and the query protein; A method comprising:

127. 1. A method for identifying a modulator of a downstream activity of Rfwd2, comprising: (a) providing a candidate modulator; (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 a candidate modulator under conditions that allow binding of Rfwd2 to the query protein; (c) measuring a downstream activity of Rfwd2, wherein a change in the downstream activity in the presence of the candidate modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of Rfwd2; A method comprising:

128. 1. A method for identifying a modulator of a downstream activity of a query protein selected from Wdr82, Ep300, Anapc13, Cul2, Cul5, Huwe1, Crebbp, Skp1a, Nedd8, Cul1, and Wdr5, comprising: (a) providing a candidate modulator; (b) contacting the query protein with Rfwd2 in the presence or absence of a candidate modulator under conditions that allow binding of the query protein to Rfwd2; (c) measuring a downstream activity of the query protein, wherein a change in the downstream activity in the presence of the candidate modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of the query protein; A method comprising:

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

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

131. 129. 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. 129. The method of claim 127 or 128, wherein the change in downstream activity is a decrease in the amount, intensity, or duration of the downstream activity.

133. 133. The method of any one of claims 126 to 132, wherein the modulator is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid.

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

135. The antigen-binding fragment may be bis-Fab, Fv, Fab, Fab'-SH, F(ab') ２ , a diabody, a linear antibody, scFv, scFab, a VH domain, or a VHH domain.

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

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

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

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

140. A method for treating an inflammatory or autoimmune disease in an individual, 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, 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 for treating an individual with cancer, an inflammatory disease, or an autoimmune disease according to the method of any one of claims 139 to 141.

143. 143. The kit of claim 142, comprising a package insert containing instructions for administering the modulator to an individual with cancer, an inflammatory disease, or an autoimmune disease.

144. 1. A method for identifying a modulator of the interaction between a protein complex comprising tyrosine-protein phosphatase non-receptor type 11 (Ptpn11) and a Ring finger and WD repeat domain 2 (Rfwd2) and a CCAAT enhancer-binding protein (Cebp) family transcription factor, comprising: (a) providing a candidate modulator; (b) contacting the protein complex with a Cebp family transcription factor in the presence or absence of a candidate modulator under conditions that allow binding of Rfwd2 to the query protein; (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 modulator compared to binding in the absence of the candidate modulator identifies the candidate modulator as a modulator of the interaction between the protein complex and the Cebp family transcription factor; A method comprising:

145. 1. A method for identifying a modulator of a downstream activity of a protein complex comprising Ptpn11 and Rfwd2, comprising: (a) providing a candidate modulator; (b) contacting the protein complex with a Cebp family transcription factor in the presence or absence of a candidate modulator under conditions that allow binding of the protein complex to the Cebp family transcription factor; (c) measuring a downstream activity of the protein complex, wherein a change in the downstream activity in the presence of the candidate modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of the protein complex; A method comprising:

146. 1. A method for identifying a modulator of a downstream activity of a Cebp family transcription factor, comprising: (a) providing a candidate modulator; (b) contacting a Cebp family transcription factor with a protein complex comprising Ptpn11 and Rfwd2 in the presence or absence of a candidate modulator under conditions that allow binding of the Cebp family transcription factor to the protein complex; (c) measuring a downstream activity of the query protein, wherein a change in the downstream activity in the presence of the candidate modulator compared to the downstream activity in the absence of the candidate modulator identifies the candidate modulator as a modulator of the downstream activity of the query protein; A method comprising:

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

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

149. 147. 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. 147. The method of claim 145 or 146, wherein the change in downstream activity is a decrease in the amount, intensity, or duration of the downstream activity.

151. 151. The method of any one of claims 144 to 150, wherein the modulator is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid.

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

153. The antigen-binding fragment may be bis-Fab, Fv, Fab, Fab'-SH, F(ab') ２ , a diabody, a linear antibody, scFv, scFab, a VH domain, or a VHH domain.

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

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

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

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

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

159. 159. The method of any one of claims 156 to 158, wherein the modulator alters the downstream activity of a protein encoded by a gene of Table 1 or Table 2 in the presence of the modulator compared to the downstream activity in the absence of the modulator.

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

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

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

163. 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. 164. The method of any one of claims 156 to 163, wherein the modulator is a proteolysis-targeting chimeric molecule (PROTAC), a small molecule, an antibody or antigen-binding fragment thereof, a peptide, a mimetic, or an inhibitory nucleic acid.

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

166. The antigen-binding fragment may be bis-Fab, Fv, Fab, Fab'-SH, F(ab') ２ , a diabody, a linear antibody, scFv, scFab, a VH domain, or a VHH domain.

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

168. 168. The method of any one of claims 156 to 167, wherein the disease or disorder associated with APCs and / or inflammation is a neurodegenerative disease, arthritis, allergy, eczema, fibrosis, asthma, lupus erythematosus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or blastic plasmacytoma dendritic cell neoplasm.

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

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

171. 171. The method of claim 170, wherein the glial cells are microglial cells, astrocytes, or oligodendrocytes.

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

173. 173. A kit comprising a modulator of a gene of Table 1 or Table 2 for treating an individual having a disease or disorder associated with APCs and / or inflammation according to the method of any one of claims 156-172.

174. 174. The kit of claim 173, comprising a package insert containing instructions for administering the modulator to an individual having a disease or disorder associated with APCs and / or inflammation.

175. 1. A method of monitoring the response of an individual having a disease or disorder associated with APCs and / or inflammation to treatment with a modulator of a gene of Table 1 or Table 2, comprising: (a) determining the expression level of a gene of Table 1 or Table 2 in a biological sample obtained from the individual at a time point after administration of a modulator; (b) comparing the expression levels of the genes of Table 1 or Table 2 in the biological sample with reference levels, thereby monitoring the response in the individual to treatment with the modulator; A method comprising:

176. 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 administration of the modulator; (ii) the expression level of the gene in a reference population; (iii) a pre-assigned expression level for the gene; or (iv) the expression level of the gene in a biological sample obtained from the individual at an earlier time point after administration of the modulator.

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

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

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