PD-1 AXIS BINDING ANTAGONIST AND TIGIT INHIBITORS FOR USE IN THE TREATMENT OF CANCER

Abstract

The present invention relates to an anti-PD-1 antagonist antibody and an anti-TIGIT antagonist antibody for use in treating or delaying the progression of cancer, reducing or inhibiting the recurrence of cancer or cancer, treating or delaying the progression of a viral infection, or reducing or inhibiting the progression of a viral infection in an individual, wherein the anti-TIGIT antagonist antibody inhibits or blocks the interaction of CD226 with TIGIT, and wherein the anti-PD-1 antagonist antibody inhibits or blocks the interaction of PD-1 and PD-L1.

Description

PD-1 SHAFT-BINDING ANTAGONIST AND TIGIT INHIBITORS FOR USE IN THE TREATMENT OF CANCER CROSS REFERENCES TO RELATED APPLICATIONS This application claims the priority benefit of the U.S. Provisional Application. No. 61 / 846,941, filed July 16, 2013, U.S. Provisional Application No. 61 / 865,582, filed August 13, 2013, U.S. Provisional Application No. 61 / 950,754, filed March 10, 2014, U.S. Provisional Application No. 61 / 985,884, filed April 29, 2014, and U.S. Provisional Application No. 61 / 992,109, filed May 12, 2014, each of which is incorporated by reference in its entirety. PRESENTATION OF THE LIST OF SEQUENCES IN ASCII TEXT FILE The content of the following ASCII text file presentation is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name: 146392025940SEQLISTING.TXT, recorded date: July 16 2014, size: 25 KB). BACKGROUND OF THE INVENTION The provision of two distinct signals to T cells is a widely accepted model for lymphocyte activation of resting T cells by antigen presenting cells (APCs). Lafferty et al, Aust. J. Exp. Biol. Med. Sel. 53: 27-42 (1975). This model further provides discrimination of self-from non-self- and immune tolerance. Bretscher et al, Science 169: 1042-1049 (1970); Bretscher, P.A., P.N.A.S. US 96: 185-190 (1999); Jenkins et al, J. Exp. Med. 165: 302-319 (1987). The primary signal, or antigen-specific signal, is transduced via the T cell receptor (TCR) following recognition of the foreign antigen peptide presented in the context of major histocompatibility complex (MHC). The second or costimulatory signal is delivered to T cells by costimulatory molecules expressed on antigen presenting cells (APCs), and induces T cells to promote clonal expansion, cytokine secretion, and function of the T cells. effector. Lenschow et al., Ann. Rev. Immunol. 14:233 (1996). In the absence of costimulation, T cells can become refractory to antigen stimulation, resulting in a tolerogenic response to either external or endogenous antigens. In the two-signal model, T cells receive both positive co-stimulatory and negative co-inhibitory signals. Regulation of such positive and negative signals is critical to maximize host protective immune responses, while maintaining immune tolerance and preventing autoimmunity. Negative signals appear to be necessary for the induction of T cell tolerance, while positive signals promote T cell activation. Both costimulatory and co-inhibitory signals are provided to antigen-exposed T cells, and the interaction between costimulatory and co-inhibitory signals is essential to control the magnitude of an immune response. Furthermore, the signals provided to T cells change as an infection or immune challenge clears, worsens, or persists, and these changes powerfully affect responding T cells and the reconfiguration of the immune response. hanonn / i zoz / e / yl - 2 The costimulatory mechanism is of therapeutic interest because manipulation of costimulatory signals has been shown to provide a means of either enhancing or terminating the cell-based immune response. Recently, it has been discovered that T cell dysfunction or anergy occurs concurrently with induced and sustained expression of the inhibitory receptor, programmed death polypeptide 1 (PD-1). As a result, therapeutic targeting of PD-1 and other molecules that signal through interactions with PD-1, such as programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2) is an area of ​​intense interest. PD-L1 is overexpressed in many cancers and is often associated with poor prognosis (Okazaki T et al., Intern. Immun. 2007 19(7):813) (Thompson RH et al., Cancer Res 2006, 66 (7):3381). Interestingly, most tumor-infiltrating T cells predominantly express PD-1, in contrast to T cells in normal tissues and T cells in peripheral blood, indicating that upregulation of PD-1 in T cells Tumor reactive cells may contribute to impaired anti-tumor immune responses (Blood 2009 114(8):1537). This may be due to exploitation of PD-L1 signaling mediated by PD-L1-expressing tumor cells interacting with PD-1-expressing T cells to result in attenuation of T cell activation and evasion. of immune surveillance (Sharpe et al., Nat Rev 2002) (Keir ME et al., 2008 Annu. Rev. Immunol. 26:677). Consequently, inhibition of the PD-L1 / PD-1 interaction may enhance CD8+ T cell-mediated destruction of tumors. Inhibition of PD-1 axis signaling through its direct ligands (e.g., PD-L1, PD-L2) has been proposed as a means of enhancing T cell immunity for cancer treatment (e.g., immune of the tumor). Furthermore, similar enhancements to T cell immunity have been observed by inhibiting the binding of PD-L1 to the binding partner B7-1. Additionally, by combining the inhibition of PD-1 signaling with other deregulated signaling pathways in tumor cells the efficacy of treatment may be further improved. There remains a need for such optimal therapy to treat, stabilize, prevent, and / or retard the development of various cancers. All references, publications, and patent applications set forth herein are hereby incorporated by reference in their entirety. SUMMARY OF THE INVENTION The present invention describes a combination treatment comprising a PD-1 axis binding antagonist and an agent that decreases or inhibits the expression and / or activity of TIGIT. Provided herein are methods of treating or slowing the progress of cancer in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits the expression and / or activity of from TIGIT. Also provided herein are methods of reducing or inhibiting cancer recurrence or cancer progression in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits the expression and / or activity of TIGIT. - 3 Also provided herein are methods of treating or slowing the progression of an immune-related disease in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits the expression and / or activity of TIGIT. Also provided herein are methods of reducing or inhibiting the progression of an immune-related disease in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits the expression and / or activity of TIGIT. In some modalities, the immune-related disease is associated with a dysfunctional T-cell disorder. In some modalities, the dysfunctional T-cell disorder is characterized by decreased sensitivity to antigenic stimulation. In some embodiments, the dysfunctional T cell disorder is characterized by T cell anergy or a decreased ability to secrete cytokines, to proliferate, or to perform cytolytic activity. In some embodiments, the dysfunctional T cell disorder is characterized by depletion of T cells. In some embodiments, the T cells are CD4+ and CD8+ T cells. In some embodiments, the immune-related disease is selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity. Also provided herein are methods of increasing, improving, or stimulating an immune response or function in an individual by administering to the individual an effective amount of a PD1 axis binding antagonist and an agent that decreases or inhibits the expression and / or activity of TIGIT. Also provided herein are methods of treating or slowing the progression of cancer in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or activity of CD226. Also provided herein are methods of reducing or inhibiting cancer recurrence or cancer progression in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or the activity of CD226. Also provided herein are methods of treating or slowing the progression of an immune-related disease in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or the activity of CD226. Also provided herein are methods of reducing or inhibiting the progression of an immune-related disease in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or the activity of CD226. In some modalities, the immune-related disease is associated with a dysfunctional T-cell disorder. In some modalities, the dysfunctional T-cell disorder is characterized by decreased sensitivity to antigenic stimulation. In some embodiments, the dysfunctional T cell disorder is characterized by T cell anergy or a decreased ability to secrete cytokines, to proliferate, or to perform cytolytic activity. In some embodiments, the dysfunctional T cell disorder is characterized by depletion of T cells. In some embodiments, the T cells are CD4+ and CD8+ T cells. In some hQHQnn / I 7O7 / E / Yl· - 4 modalities, the immune related disease is selected from the group consisting of unresolved acute infection, chronic infection and tumor immunity. Also provided herein are methods of increasing, improving, or stimulating an immune response or function in an individual by administering to the individual an effective amount of a PD1 axis binding antagonist and an agent that modulates the expression and / or activity of CD226. In some embodiments, the agent that modulates CD226 expression and / or activity has the ability to increase and / or stimulate CD226 expression and / or activity. In some embodiments, the agent that modulates CD226 expression and / or activity is selected from an agent that inhibits and / or blocks the interaction of CD226 with TIGIT, an antagonist of TIGIT expression and / or activity, an antagonist of the expression and / or activity of PVR, an agent that inhibits and / or blocks the interaction of TIGIT with PVR, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR. In some embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. . In some embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is an anti-TIGIT antibody or an antigen-binding fragment thereof. In some embodiments, the antagonist of TIGIT expression and / or activity is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody or an antigen-binding fragment thereof. In some embodiments, the antagonist of PVR expression and / or activity is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks the interaction of TIGIT with PVR is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. . In some embodiments, the agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid , and an inhibitory polypeptide. The present invention also describes a combination treatment comprising an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent that decreases or inhibits one or more additional coinhibitor immune receptors. Provided herein are methods of increasing, improving, or stimulating an immune response or function in an individual by administering to the individual an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent that decreases or inhibits one. or more additional immune co-inhibitory receptors. franconn / Lznz / E / YL - 5 In some embodiments, the one or more additional immune co-inhibitory receptors are selected from the group consisting of PD-1, CTLA-4, LAG3, TIM3, BTLA and VISTA. In some embodiments, the one or more additional immune co-inhibitory receptors are selected from the group of PD-1, CTLA-4, LAG3 and TIM3. The present invention also describes a combination treatment comprising an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent that increases or activates one or more additional immune costimulatory receptors. Provided herein are methods of increasing, improving, or stimulating an immune response or function in an individual by administering to the individual an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent that increases or activates one. or more additional immune co-stimulatory receptors. In some embodiments, the one or more additional costimulatory immune receptors are selected from the group consisting of CD226, OX-40, CD28, CD27, CD137, HVEM, and GITR. In some embodiments, the one or more additional costimulatory immune receptors are selected from the group of CD226, OX-40, CD27, CD137, HVEM, and GITR. In some embodiments, the one or more additional immune costimulatory receptors are selected from the group consisting of OX-40 and CD27. In some embodiments, any of the above methods further comprises administering at least one chemotherapeutic agent. In some embodiments, the individual in any of the above methods has cancer. In some embodiments, the individual in any of the above methods is a human. In some embodiments, CD4 and / or CD8 T cells in the individual have increased or enhanced pre-stimulation, activation, proliferation, cytokine release and / or cytolytic activity relative to prior to administration of the combination. In some modalities, the number of CD4 and / or CD8 T cells is elevated relative to before the administration of the combination. In some modalities, the number of activated CD4 and / or CD8 T cells is elevated relative to prior to administration of the combination. In some embodiments, activated CD4 and / or CD8 T cells are characterized by γ-IFN-producing CD4 and / or CD8 T cells and / or by enhanced cytolytic activity relative to prior to administration of the combination. In some embodiments, CD4 and / or CD8 T cells exhibit increased release of cytokines selected from the group consisting of IFN-γ, TNF-α, and interleukins. In some embodiments, the CD4 and / or CD8 T cell is an effector memory T cell. In some embodiments, the effector memory CD4 and / or CD8 T cell is characterized by γIFN-producing CD4 and / or CD8 T cells and / or by enhanced cytolytic activity. In some embodiments, the effector memory CD4 and / or CD8 Y cell is characterized as having the expression of CD44altaCD62Lbaia. In some embodiments, the cancer, in any of the above methods, has high levels of T cell infiltration. In some embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is hanonn / i zoz / e / yl - 6 selected from the group consisting of an antagonist of the expression and / or activity of TIGIT, an antagonist of the expression and / or activity of PVR, and an agent that inhibits the interaction and / or intracellular signaling mediated by the union of TIGIT to PVR. In some embodiments, the antagonist of TIGIT expression and / or activity is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the antagonist of PVR expression and / or activity is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the agent that inhibits intracellular signaling mediated by TIGIT binding to PVR is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an acid inhibitory nucleic acid and an inhibitory polypeptide. In some embodiments, the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody or an antigen-binding fragment thereof. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof comprises at least one HVR comprising an amino acid sequence selected from the amino acid sequences KSSQSLYYSGVKENLLA (SEQ ID NO: 1), ASIRFT (SEQ ID NO: 2 ), QQGINNPLT (SEQ ID NO: 3), GFTFSSFTMH (SEQ ID NO: 4), FIRSGSGIVFYADAVRG (SEQ ID NO: 5), and RPLGHNTFDS (SEQ ID NO: 6) or RSSQSLVNSYGNTFLS (SEQ ID NO: 7), GISNRFS ( SEQ ID NO: 8), LQGTHQPPT (SEQ ID NO: 9), GYSFTGHLMN (SEQ ID NO: 10), LIIPYNGGTSYNQKFKG (SEQ ID NO: 11), and GLRGFYAMDY (SEQ ID NO: 12). In some embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence described in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO: 13) or DWLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGSGTDFTLKIS TIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO: 14). In some embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence described in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFTISRDNAKNLLF LQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO: 1 5) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLTVDKSSSTAY MELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO: 16). In some embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence described in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS hQHQnn / Lznz / E / Yli - 7 PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO: 13) or DWLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGSGTDFTLKIS TIKPEDLGMYYCL QGTHQPPTFGPGTKLEVK (SEQ ID NO: 14) and the heavy chain of the antibody comprises the amino acid sequence described in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFTISRDNAKNLLF LQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO: 15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLTVDKSSSTAY MELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO: 16). In some embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof, wherein the antibody is selected from a humanized antibody, a chimeric antibody, a bispecific antibody, a heteroconjugate antibody, and an immunotoxin. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof comprises at least one HVR that is at least 90% identical to an HVR described in any of KSSQSLYYSGVKENLLA (SEQ ID NO: 1), ASIRFT (SEQ ID NO : 2), QQGINNPLT (SEQ ID NO: 3), GFTFSSFTMH (SEQ ID NO: 4), FIRSGSGIVFYADAVRG (SEQ ID NO: 5), and RPLGHNTFDS (SEQ ID NO: 6) or RSSQSLVNSYGNTFLS (SEQ ID NO: 7), GISNRFS (SEQ ID NO: 8), LQGTHQPPT (SEQ ID NO: 9), GYSFTGHLMN (SEQ ID NO: 10), LIIPYNGGTSYNQKFKG (SEQ ID NO: 11), and GLRGFYAMDY (SEQ ID NO: 12). In some embodiments, the anti-TIGIT antibody or fragment thereof comprises light chain and / or heavy chain comprising amino acid sequences at least 90% identical to the amino acid sequences described in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLUYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPL TFGDGTKLEIKR (SEQ ID NO: 13) or DWLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGSGTDFTLKIS TIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO: 14), or EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFTISRDNAKNLLF LQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO: 15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLTVDKSSSTAY MELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO: 16), respectively. In some embodiments, the PD-1 axis binding antagonist is selected from the group consisting of a PD-1 binding antagonist, a PD-L1 binding antagonist, and a PD-L2 binding antagonist. In some embodiments, the PD-1 axis binding antagonist is a PD-1 binding antagonist. In some embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to its ligand binding partners. In some embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1. In some embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. In some embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. In some embodiments, the PD-1 binding antagonist is an antibody. In some embodiments, the PD-1 binding antagonist is MDX-1106 (nivolumab). In some - 8 modalities, the PD-1 binding antagonist is Merck 3475 (lambrolizumab). In some modalities, the PD-1 binding antagonist is CT-011 (pidilizumab). In some embodiments, the PD-1 binding antagonist is AMP-224. In some embodiments, the PD-1 axis binding antagonist is a PD-L1 binding antagonist. In some embodiments, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1. In some embodiments, the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1. In some embodiments, the PDL1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1. In some embodiments, the PD-L1 binding antagonist is an antibody. In some embodiments, the PD-L1 binding antagonist is selected from the group consisting of: YW243.55.S70, MPDL3280A, MDX-1105, and MEDI 4736. In some embodiments, the anti-PD-L1 antibody comprises a heavy chain comprising the HVR-H1 sequence from GFTFSDSWIH (SEQ ID NO: 17), the HVR-H2 sequence from AWISPYGGSTYYADSVKG (SEQ ID NO: 18), and the sequence RHWPGGFDY HVR-H3 (SEQ ID NO: 19); and a light chain comprising the HVR-L1 sequence from RASQDVSTAVA (SEQ ID NO: 20), the HVR-L2 sequence from SASFLYS (SEQ ID NO: 21), and the HVR-L3 sequence from QQYLYHPAT (SEQ ID NO: 22 ). In some embodiments, the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO: 23) and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 24). In some embodiments, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some embodiments, the PD-L2 binding antagonist is an antibody. In some embodiments, the PD-L2 binding antagonist is an immunoadhesin. In some embodiments, the cancer to be treated is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, renal cell cancer, colorectal cancer, ovarian cancer, breast cancer, pancreatic cancer, gastric carcinoma, bladder cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer, thyroid cancer, sarcoma, prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphomas, myelomas, mycosis fungoides, cancer Merkel cell, and other hematological diseases. In some embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered continuously. In some embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered intermittently. In some embodiments, the agent that decreases or inhibits the expression and / or activity of TIGIT is administered before the PD-1 axis binding antagonist. In some modalities, the agent that decreases or inhibits the expression and / or activity of TIGIT is administered concurrently with the axis binding antagonist PDhanonn / ι znz / E / Yl· 1. In some embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered after the PD-1 axis binding antagonist. Also provided herein are kits comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or or the activity of TIGIT to treat or slow the progression of cancer in an individual. Also provided herein are kits comprising a PD-1 axis-binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity, and a package insert comprising instructions for using the PD-1 axis-binding antagonist. PD-1 axis and the agent that decreases or inhibits the expression and / or activity of TIGIT to treat or slow the progression of cancer in an individual. Also provided herein are kits comprising an agent that decreases or inhibits TIGIT expression and / or activity and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and / or activity in combination with a PD-1 axis binding antagonist to treat or slow the progression of cancer in an individual. Also provided herein are kits comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or or the activity of TIGIT to enhance the immune function of an individual having cancer. Also provided herein are kits comprising a PD-1 axis-binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity, and a package insert comprising instructions for using the PD-1 axis-binding antagonist. PD-1 axis and the agent that decreases or inhibits the expression and / or activity of TIGIT to increase the immune function of an individual having cancer. Also provided herein are kits comprising an agent that decreases or inhibits TIGIT expression and / or activity and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and / or activity in combination with a PD-1 axis binding antagonist to increase the immune function of an individual having cancer. Also provided herein are kits comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that modulates expression and / or CD226 activity to treat or slow the progression of cancer in an individual. Also provided herein are kits comprising a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity, and a package insert comprising instructions for using the PD axis binding antagonist. -1 and the agent that modulates the expression and / or activity of CD226 to treat or slow the progression of cancer in an individual. Also provided herein are kits comprising an agent that modulates franonn / Lznz / E / YL expression. - 10 and / or CD226 activity and a package insert comprising instructions for using the agent that modulates CD226 expression and / or activity in combination with a PD-1 axis binding antagonist to treat or slow progression of cancer in an individual. Also provided herein are kits comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that modulates expression and / or CD226 activity to enhance the immune function of an individual having cancer. Also provided herein are kits comprising a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity, and a package insert comprising instructions for using the PD axis binding antagonist. -1 and the agent that modulates the expression and / or activity of CD226 to increase the immune function of an individual having cancer. Also provided herein are kits comprising an agent that modulates CD226 expression and / or activity and a package insert comprising instructions for using the agent that modulates CD226 expression and / or activity in combination with an antagonist. binding to the PD-1 axis to increase the immune function of an individual having cancer. In some embodiments, the kits comprise a PD-1 axis binding antagonist that is an anti-PD-L1 antibody. In some embodiments, the kits comprise a PD-1 axis binding antagonist that is an anti-PD-L1 antibody. In some embodiments, kits comprising the agent that decreases or inhibits TIGIT expression and / or activity is selected from the group consisting of an antagonist of TIGIT expression and / or activity, an antagonist of TIGIT expression and / or or the activity of PVR, and an agent that inhibits the interaction and / or intracellular signaling mediated by the binding of TIGIT to PVR. In some embodiments, the kits comprise an antagonist of TIGIT expression and / or activity that is an anti-TIGIT antibody or an antigen-binding fragment thereof. In some embodiments, the kits comprise an agent that modulates CD226 expression and / or activity that has the ability to increase and / or stimulate CD226 expression and / or activity. In some embodiments, the kits comprise an agent that modulates the expression and / or activity of CD226 that is selected from an agent that inhibits and / or blocks the interaction of CD226 with TIGIT, an antagonist of the expression and / or activity of TIGIT, an antagonist of PVR expression and / or activity, an agent that inhibits and / or blocks the interaction of TIGIT with PVR, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR. In some embodiments, the kits comprise the agent that inhibits and / or blocks the interaction of CD226 with TIGIT and / or the antagonist of TIGIT expression and / or activity which is an anti-TIGIT antibody or antigen-binding fragment. of the same. In certain aspects, the present disclosure provides a method of treating or slowing the progression of cancer in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits the expression and / or TIGIT activity. In other respects, the present - 11 disclosure provides for the use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for treating or slowing the progression of cancer in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides the use of an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT, in the manufacture of a medicament for treating or retarding the progression of cancer in an individual, in wherein the agent that decreases or inhibits TIGIT expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in treating or delaying the progression of cancer in combination with an agent that decreases or inhibits the expression and / or the TIGIT activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits the expression and / or activity of TIGIT for use in treating or delaying the progression of cancer in combination with an axis binding antagonist. PS-1. In other aspects, the present disclosure provides a method of reducing or inhibiting cancer recurrence or cancer progression in an individual, comprising administering to the individual an effective amount of PD-1 axis binding antagonist and an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides the use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for reducing or inhibiting cancer recurrence or cancer progression in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides the use of an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT in the manufacture of a medicament for reducing or inhibiting cancer recurrence or cancer progression in an individual, wherein the agent that decreases or inhibits TIGIT expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in reducing or inhibiting cancer recurrence or cancer progression in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits the expression and / or activity of TIGIT for use in reducing or inhibiting cancer recurrence or cancer progression in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a method of treating or slowing the progression of an immune-related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides the use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for treating or retarding the progression of an immune-related disease in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. In other respects, the present disclosure franonn / Lznz / E / YL - 12 provides for the use of an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT in the manufacture of a medicament for treating or retarding the progression of an immune-related disease in an individual, wherein the agent that decreases or inhibits the expression and / or activity of TIGIT is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in treating or delaying the progression of an immune-related disease in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits the expression and / or activity of TIGIT for use in treating or delaying the progression of an immune-related disease in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a combination comprising an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a method of reducing or inhibiting the progression of an immune-related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides the use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for reducing or inhibiting the progression of an immune-related disease in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides the use of an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT in the manufacture of a medicament for reducing or inhibiting the progression of an immune-related disease in an individual, wherein the agent that decreases or inhibits TIGIT expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in reducing or inhibiting the progression of an immune-related disease in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits the expression and / or activity of TIGIT for use in reducing or inhibiting the progression of an immune-related disease in combination with a PD-1 axis binding antagonist. In certain modalities that may be combined with any of the foregoing modalities, the immune-related disease is associated with a dysfunctional T-cell disorder. In certain modalities that may be combined with any of the foregoing modalities, the immune-related disease is a viral infection. In certain modalities that can be combined with any of the preceding modalities, the viral infection is a chronic viral infection. In certain modalities that can be combined with hQHQnn / I 7O7 / E / Yl· In any of the foregoing modalities, dysfunctional T-cell disorder is characterized by decreased sensitivity to antigenic stimulation. In certain modalities that may be combined with any of the foregoing modalities, the dysfunctional T cell disorder is characterized by T cell anergy or a decreased ability to secrete cytokines, to proliferate, or to perform cytolytic activity. In certain modalities that may be combined with any of the foregoing modalities, the dysfunctional T cell disorder is characterized by depletion of T cells. In certain modalities that may be combined with any of the foregoing modalities, the T cells are CD4+ T cells and CD8+. In certain modalities that may be combined with any of the preceding modalities, the immune-related disease is selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity. In other aspects, the present disclosure provides a method of increasing, improving, or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides the use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the PD-1 binding agent PD-1 axis is used in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides the use of an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, in wherein the agent that decreases or inhibits TIGIT expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in enhancing or stimulating an immune response or function in combination with an agent that decreases or inhibits the expression and / or TIGIT activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits the expression and / or activity of TIGIT for use in enhancing or stimulating an immune response or function in combination with an antagonist binding to TIGIT. PD-1 shaft. In other aspects, the present disclosure provides a combination comprising an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a method of treating or slowing the progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or CD226 activity. In other aspects, the present disclosure provides the use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for treating or slowing the progression of cancer in an individual, wherein the axis binding agent PD-1 is used in combination with an agent that modulates the expression and / or activity of CD226. In other aspects, the present disclosure provides the use of an effective amount of an agent that modulates the expression and / or activity of CD226 in the manufacture of a medicament for treating or retarding the progression of cancer in an individual, wherein the agent that modulates the expression and / or activity of CD226 is used in combination with a PD-1 axis binding antagonist. hanonn / 1znz / E / YL - 14 In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in treating or delaying the progression of cancer in combination with an agent that modulates the expression and / or the CD226 activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that modulates the expression and / or activity of CD226 for use in treating or delaying the progression of cancer in combination with a PD-axis binding antagonist. 1. In other aspects, the present disclosure provides a method of reducing or inhibiting cancer recurrence or cancer progression in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or activity of CD226. In other aspects, the present disclosure provides the use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for reducing or inhibiting cancer recurrence or cancer progression in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that modulates the expression and / or activity of CD226. In other aspects, the present disclosure provides the use of an effective amount of an agent that modulates the expression and / or activity of CD226 in the manufacture of a medicament for reducing or inhibiting cancer recurrence or cancer progression in an individual. , wherein the agent that modulates the expression and / or activity of CD226 is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in reducing or inhibiting cancer recurrence or cancer progression in combination with an agent that modulates the expression and / or the activity of CD226. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that modulates the expression and / or activity of CD226 for use in reducing or inhibiting cancer recurrence or cancer progression in combination with an antagonist of CD226. union to the PD-1 shaft. In other aspects, the present disclosure provides a method of treating or slowing the progression of an immune-related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or activity of CD226. In other aspects, the present disclosure provides the use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for treating or retarding the progression of an immune-related disease in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that modulates the expression and / or activity of CD226. In other aspects, the present disclosure provides the use of an effective amount of an agent that modulates the expression and / or activity of CD226 in the manufacture of a medicament for treating or retarding the progression of an immune-related disease in an individual. , wherein the agent that modulates the expression and / or activity of CD226 is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in treating or delaying the progression of an immune-related disease in combination with an agent that modulates the expression and / or the activity of CD226. In other aspects, the present description provides a pharmaceutical composition comprising an agent that modulates the expression and / or hQHQnn / I 7O7 / E / Yl· - 15 the activity of CD226 for use in treating or delaying the progression of an immune related disease in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a combination comprising an effective amount of a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides a method of reducing or inhibiting the progression of an immune-related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or activity of CD226. In other aspects, the present disclosure provides the use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for reducing or inhibiting the progression of an immune-related disease in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that modulates the expression and / or activity of CD226. In other aspects, the present disclosure provides the use of an effective amount of an agent that modulates the expression and / or activity of CD226 in the manufacture of a medicament for reducing or inhibiting the progression of an immune-related disease in an individual. , wherein the agent that modulates the expression and / or activity of CD226 is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis-binding antagonist for use in reducing or inhibiting the progression of an immune-related disease in combination with an agent that modulates the expression and / or the activity of CD226. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that modulates the expression and / or activity of CD226 for use in reducing or inhibiting the progression of an immune-related disease in combination with an antagonist of CD226. union to the shaft PD-1. In certain modalities that may be combined with any of the foregoing modalities, the immune-related disease is associated with a dysfunctional T-cell disorder. In certain modalities that may be combined with any of the foregoing modalities, the immune-related disease is a viral infection. In certain modalities that can be combined with any of the preceding modalities, the viral infection is a chronic viral infection. In certain modalities that may be combined with any of the foregoing modalities, the dysfunctional T-cell disorder is characterized by decreased sensitivity to antigenic stimulation. In certain modalities that may be combined with any of the foregoing modalities, T cell dysfunctional disorder is characterized by T cell anergy, or a decreased ability to secrete cytokines, to proliferate, or to perform cytolytic activity. In certain modalities that may be combined with any of the foregoing modalities, the dysfunctional T cell disorder is characterized by depletion of T cells. In certain modalities that may be combined with any of the foregoing modalities, the T cells are CD4+ T cells and CD8+. In certain modalities that may be combined with any of the foregoing modalities, the immune-related disease is selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity. In other aspects, the present disclosure provides a method for increasing, improving or hQHQnn / Lznz / E / Yli - 16 stimulating an immune response or function in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or activity of CD226. In other aspects, the present disclosure provides the use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the PD-1 binding agent PD-1 axis is used in combination with an agent that modulates the expression and / or activity of CD226. In other aspects, the present disclosure provides the use of an effective amount of an agent that modulates the expression and / or activity of CD226 in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the agent that modulates the expression and / or activity of CD226 is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in enhancing or stimulating an immune response or function in combination with an agent that modulates expression and / or activity. from CD226. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that modulates the expression and / or activity of CD226 for use in enhancing or stimulating an immune response or function in combination with a PD axis binding antagonist. -1. In other aspects, the present disclosure provides a combination comprising an effective amount of a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is an agent that increases and / or stimulates CD226 expression and / or activity. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates the expression and / or activity of CD226 is an agent that increases and / or stimulates the interaction of CD226 with PVR. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates the expression and / or activity of CD226 is an agent that increases and / or stimulates intracellular signaling mediated by the binding of CD226 to PVR. In certain modalities that can be combined with any of the preceding modalities, the agent that modulates the expression and / or activity of CD226 is selected from the group consisting of an agent that inhibits and / or blocks the interaction of CD226 with TIGIT, an antagonist of TIGIT expression and / or activity, an antagonist of PVR expression and / or activity, an agent that inhibits and / or blocks the interaction of TIGIT with PVR, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL2, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL3, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR, an agent that inhibits and / or blocks intracellular signaling mediated by TIGIT binding to PVRL2, an agent that inhibits and / or blocks intracellular signaling mediated by TIGIT binding to PVRL3, and combinations thereof. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is an agent that inhibits and / or blocks the interaction of CD226 with TIGIT. In certain modalities that may be combined with any of the preceding modalities, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, a hQDQnn / I 7O7 / E / Yl nucleic acid - 17 inhibitor, or an inhibitor polypeptide. In certain embodiments that may be combined with any of the preceding embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is an anti-TIGIT antibody or an antigen-binding fragment thereof. In certain embodiments that may be combined with any of the preceding embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is an inhibitory nucleic acid selected from the group consisting of an antisense polynucleotide, an interfering RNA, an RNA catalytic, and an RNA-DNA chimera. In certain modalities that can be combined with any of the preceding modalities, the antisense polynucleotide is targeted to TIGIT. In certain modalities that can be combined with any of the preceding modalities, the interfering RNA is focused towards TIGIT. In certain modalities that can be combined with any of the preceding modalities, the catalytic RNA is focused towards TIGIT. In certain modalities that can be combined with any of the preceding modalities, the RNA-DNA chimera is targeted towards TIGIT. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is an antagonist of TIGIT expression and / or activity. In certain embodiments that may be combined with any of the preceding embodiments, the antagonist of TIGIT expression and / or activity is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, a nucleic acid inhibitor, and an inhibitor polypeptide. In certain embodiments that may be combined with any of the preceding embodiments, the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody or an antigen-binding fragment thereof. In certain embodiments that may be combined with any of the preceding embodiments, the antagonist of TIGIT expression and / or activity is an inhibitory nucleic acid selected from the group consisting of an antisense polynucleotide, an interfering RNA, a catalytic RNA, and an RNA-DNA chimera. In certain embodiments that may be combined with any of the preceding embodiments, the antagonist of PVR expression and / or activity is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody, or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In certain modalities that may be combined with any of the preceding modalities, the agent that inhibits and / or blocks the interaction of TIGIT with PVR is selected from the group consisting of a small molecule inhibitor, inhibitory antibody, or antigen-binding fragment of the TIGIT. itself, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In certain modalities that may be combined with any of the preceding modalities, the agent that inhibits and / or blocks the interaction of TIGIT with PVRL2 is selected from the group consisting of a small molecule inhibitor, inhibitory antibody, or antigen-binding fragment of the itself, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In certain embodiments that may be combined with any of the preceding modalities, the agent that inhibits and / or blocks the interaction of TIGIT with PVRL3 is selected from the group consisting of a small molecule inhibitor, inhibitory antibody, or antigen-binding fragment of the itself, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In certain modalities that may be combined with any of the preceding modalities, the agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR is selected from the group consisting of a small molecule inhibitor, a hQHQnn / Lznz / E / Yli - 18 inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In certain modalities that may be combined with any of the preceding modalities, the agent that inhibits and / or blocks the interaction of TIGIT with PVRL2 is selected from the group consisting of a small molecule inhibitor, inhibitory antibody, or antigen-binding fragment of the itself, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In certain embodiments that may be combined with any of the preceding modalities, the agent that inhibits and / or blocks the interaction of TIGIT with PVRL3 is selected from the group consisting of a small molecule inhibitor, inhibitory antibody, or antigen-binding fragment of the itself, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In other aspects, the present disclosure provides a method of increasing, improving, or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT and a agent that decreases or inhibits one or more co-inhibitory receptors of additional immunity. In other aspects, the present disclosure provides the use of an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, in wherein the agent that decreases or inhibits the expression and / or activity of TIGIT is used in combination with an agent that decreases or inhibits one or more other receptor co-inhibitors of immunity. In other aspects, the present disclosure provides the use of an effective amount of an agent that decreases or inhibits one or more additional co-inhibitory receptors of immunity in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the agent that decreases or inhibits one or more additional receptor co-inhibitors of immunity is used in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits the expression and / or activity of TIGIT for use in enhancing or stimulating an immune response or function in combination with an agent that decreases or inhibits one or more co-inhibitory receptors of additional immunity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits one or more additional receptor co-inhibitors of immunity for use in enhancing or stimulating an immune response or function in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides a combination comprising an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent that decreases or inhibits one or more additional receptor co-inhibitors of immunity. In certain modalities that may be combined with any of the preceding modalities, the one or more additional receptor immunity co-inhibitors are selected from the group consisting of PD-1, CTLA-4, LAG3, TIM3, BTLA, VISTA, B7H4, and CD96. In certain modalities that may be combined with any of the preceding modalities, the one or more additional receptor co-inhibitors of immunity are selected from the group consisting of PD-1, CTLA-4, LAG3, and TIM3. In other aspects, the present disclosure provides a method of increasing, improving or stimulating an immune response or function in an individual comprising administering to the individual an effective amount hanonn / i zoz / e / yl - 19 of an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent that increases or activates one or more co-stimulatory receptors of additional immunity. In other aspects, the present disclosure provides the use of an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, in wherein the agent that decreases or inhibits TIGIT expression and / or activity is used in combination with an agent that increases or activates one or more additional costimulatory immune receptors. In other aspects, the present disclosure provides the use of an effective amount of an agent that increases or activates one or more additional immune costimulatory receptors in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the agent that increases or activates one or more additional immune co-stimulatory receptors is used in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits the expression and / or activity of TIGIT for use in enhancing or stimulating an immune response or function in combination with an agent that increases or activates one or more additional immune costimulatory receptors. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that increases or activates one or more additional co-stimulatory receptors of immunity for use in enhancing or stimulating an immune response or function in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. In other aspects, the present disclosure provides a combination comprising an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent that increases or activates one or more additional costimulatory immune receptors. In certain modalities that may be combined with any of the preceding modalities, the one or more additional costimulatory immune receptors are selected from the group consisting of CD226, OX-40, CD28, CD27, CD137, HVEM, GITR, MICA, ICOS , NKG2D, and 2B4. In certain modalities that may be combined with any of the preceding modalities, the one or more additional costimulatory immune receptors are selected from the group consisting of CD226, OX-40, CD27, CD137, HVEM, and GITR. In certain modalities that may be combined with any of the foregoing modalities, the one or more additional immune co-stimulatory receptors are selected from the group consisting of OX-40 and CD27. In certain modalities that may be combined with any of the foregoing modalities, the method further comprises administering at least one chemotherapeutic agent. In certain modalities that can be combined with any of the preceding modalities, the individual has cancer. In certain modalities that may be combined with any of the preceding modalities, the individual is a human. In certain modalities that may be combined with any of the foregoing modalities, CD4 and / or CD8 T cells in the individual have increased or enhanced pre-stimulation, activation, proliferation, cytokine release and / or cytolytic activity relative to before the combination administration. In certain modalities that can be combined with any of the preceding modalities, the number of CD4 and / or CD8 T cells is elevated relative to before the administration of the combination. In certain modalities that can be combined with any hanonn / i zoz / e / yl - 20 of the preceding modalities, the number of activated CD4 and / or CD8 T cells is high in relation to before the administration of the combination. In certain modalities that may be combined with any of the preceding modalities, activated CD4 and / or CD8 T cells are characterized by y-IFN+ producing CD4 and / or CD8 T cells and / or by enhanced cytolytic activity relative to before administration of the combination. In certain modalities which may be combined with any of the preceding modalities, CD4 and / or CD8 T cells exhibit increased release of cytokines selected from the group consisting of I FN-y, TNF-α and interleukins. In certain modalities that can be combined with any of the preceding modalities, the CD4 and / or CD8 T cells are effector memory T cells. In certain embodiments that may be combined with any of the preceding embodiments, effector memory CD4 and / or CD8 T cells are characterized by Y-IFN+ producing CD4 and / or CD8 T cells and / or by enhanced cytolytic activity. In certain embodiments that may be combined with any of the foregoing embodiments, effector memory CD4 and / or CD8 T cells are characterized as having CD44highCD62Llow expression. In certain modalities that can be combined with any of the foregoing modalities, the cancer has high levels of T cell infiltration. In certain modalities that can be combined with any of the foregoing modalities, the agent that decreases or inhibits the expression and / or activity of TIGIT is selected from the group consisting of an antagonist of TIGIT expression and / or activity, an antagonist of PVR expression and / or activity, an agent that inhibits and / or blocks the interaction of TIGIT with PVR, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL2, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL3, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVRL2, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVRL3, and combinations thereof. In certain modalities that may be combined with any of the preceding modalities, the antagonist of TIGIT expression and / or activity is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody, or an antigen-binding fragment thereof. , an aptamer, an inhibitory nucleic acid and an inhibitory polypeptide. In certain embodiments that may be combined with any of the preceding embodiments, the antagonist of PVR expression and / or activity is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody, or an antigen-binding fragment of the itself, an aptamer, an inhibitory nucleic acid and an inhibitory polypeptide. In certain modalities that may be combined with any of the preceding modalities, the agent that inhibits and / or blocks the interaction of TIGIT with PVR is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody, or an antigen-binding fragment. thereof, an aptamer, an inhibitory nucleic acid and an inhibitory polypeptide. In certain modalities that can be combined with any of the preceding modalities, the agent that inhibits and / or blocks the interaction of TIGIT with PVRL2 is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody, or an antigen-binding fragment. thereof, an aptamer, an inhibitory nucleic acid and an inhibitory polypeptide. In certain modalities that can be combined with any of the preceding modalities, the agent that inhibits and / or blocks the interaction of TIGIT with PVRL3 is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody, or a - 21 antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid and an inhibitory polypeptide. In certain modalities that may be combined with any of the preceding modalities, the agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody, or a antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid and an inhibitory polypeptide. In certain modalities that may be combined with any of the preceding modalities, the agent that inhibits and / or blocks intracellular signaling mediated by TIGIT binding to PVRL2 is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody, or a antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid and an inhibitory polypeptide. In certain modalities that may be combined with any of the preceding modalities, the agent that inhibits and / or blocks intracellular signaling mediated by TIGIT binding to PVRL3 is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody, or a antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid and an inhibitory polypeptide. In certain embodiments that may be combined with any of the preceding embodiments, the antagonist of TIGIT expression and / or activity is an inhibitory nucleic acid selected from the group consisting of an antisense polynucleotide, an interfering RNA, a catalytic RNA, and an RNA-DNA chimera. In certain modalities that can be combined with any of the preceding modalities, the antisense polynucleotide is targeted to TIGIT. In certain modalities that can be combined with any of the preceding modalities, the interfering RNA is focused towards TIGIT. In certain modalities that can be combined with any of the preceding modalities, the catalytic RNA is focused towards TIGIT. In certain modalities that can be combined with any of the preceding modalities, the RNA-DNA chimera is targeted towards TIGIT. In certain embodiments that may be combined with any of the preceding embodiments, the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody or an antigen-binding fragment thereof. In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof comprises at least one HVR comprising an amino acid sequence selected from amino acid sequences (1) KSSQSLYYSGVKENLLA (SEQ ID NO: 1), ASIRFT (SEQ ID NO: 2), QQGINNPLT (SEQ ID NO: 3), GFTFSSFTMH (SEQ ID NO: 4), FIRSGSGIVFYADAVRG (SEQ ID NO: 5), and RPLGHNTFDS (SEQ ID NO: 6 ); or (2) RSSQSLVNSYGNTFLS (SEQ ID NO: 7), GISNRFS (SEQ ID NO: 8), LQGTHQPPT (SEQ ID NO: 9), GYSFTGHLMN (SEQ ID NO: 10), LIIPYNGGTSYNQKFKG (SEQ ID NO: 11), and GLRGFYAMDY (SEQ ID NO: 12). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof, wherein the antibody light chain comprises the amino acid sequence described in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTF GDGTKLEIKR (SEQ ID NO: 13 ) or DWLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGSGTDFTLKIS TIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO: 14). In certain modalities that can be combined with hQHQnn / Lznz / E / Yli - 22 any of the preceding modalities, the anti-TIGIT antibody or an antigen-binding fragment thereof, wherein the antibody heavy chain comprises the amino acid sequence described in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFTISRDNAKNLLF LQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTL VTVSS (SEQ ID NO: 15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLTVDKSSSTA YMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO: 16). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof, wherein the antibody light chain comprises the amino acid sequence described in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTF GDGTKLEIKR (SEQ ID NO: 13 ) or DWLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGSGTDFTLKIS TIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO: 14), and the heavy chain of antibodies comprises the amino acid sequence described in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFTISRDNAKNLLF LQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO: 15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLTVDKSSSTA YMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO: 16). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof, wherein the antibody is selected from the group consisting of a humanized antibody, a chimeric antibody, a bispecific antibody , a heteroconjugate antibody, and an immunotoxin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof comprises at least one HVR that is at least 90% identical to an HVR described in any of (1) KSSQSLYYSGVKENLLA (SEQ ID NO: 1), ASIRFT (SEQ ID NO: 2), QQGINNPLT (SEQ ID NO: 3), GFTFSSFTMH (SEQ ID NO: 4), FIRSGSGIVFYADAVRG (SEQ ID NO: 5), and RPLGHNTFDS (SEQ ID NO :6); or (2) RSSQSLVNSYGNTFLS (SEQ ID NO: 7), GISNRFS (SEQ ID NO: 8), LQGTHQPPT (SEQ ID NO: 9), GYSFTGHLMN (SEQ ID NO: 10), LIIPYNGGTSYNQKFKG (SEQ ID NO: 11), and GLRGFYAMDY (SEQ ID NO: 12). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or fragment thereof comprises the light chain comprising amino acid sequences at least 90% identical to the amino acid sequences described in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFC QQGINNPLTFGDGTKLEIKR (SEQ ID NO: 13) or DWLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGSGTDFTLKIS TIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO: 14); and / or the heavy chain comprising amino acid sequences at least 90% identical to the amino acid sequences described in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFTISRDNAKNLLF LQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO: 15) or franconn / Lznz / E / YL - 23 EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLTVDKSSSTA YMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO: 16). In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is selected from the group consisting of a PD-1 binding antagonist, a PD-L1 binding antagonist, and a PD-L1 antagonist. binding to PD-L2. In certain embodiments that may be combined with any of the foregoing embodiments, the PD-1 axis binding antagonist is a PD-1 binding antagonist. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to its ligand-binding partners. In certain modalities that can be combined with any of the preceding modalities, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1. In certain modalities that can be combined with any of the preceding modalities, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. In certain modalities that can be combined with any of the preceding modalities, the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist is an antibody. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist is MDX-1106. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist is MK-3475. In certain embodiments that may be combined with any of the foregoing embodiments, the PD-1 binding antagonist is CT-011. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist is AMP-224. In certain embodiments that may be combined with any of the foregoing embodiments, the PD-1 axis binding antagonist is a PD-L1 binding antagonist. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L1 binding antagonist is selected from the group consisting of YW243.55.S70, MPDL3280A, MDX-1105, and MEDI4736. In certain embodiments that may be combined with any of the preceding embodiments, the anti-PD-L1 antibody comprises a heavy chain comprising the HVR-H1 sequence from GFTFSDSWIH (SEQ ID NO: 17), the HVR-H2 sequence from AWISPYGGSTYYADSVKG (SEQ ID NO: 18), and the HVR-H3 sequence of RHWPGGFDY (SEQ ID NO: 19); and a light chain comprising the HVR-L1 sequence from RASQDVSTAVA (SEQ ID NO: 20), the HVR-L2 sequence from SASFLYS (SEQ ID NO: 21), and the HVR-L3 sequence from QQYLYHPAT (SEQ ID NO: 22 ). In certain embodiments that may be combined with any of the preceding embodiments, the anti-PD-L1 antibody comprises a variable heavy chain region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA hQHQnn / Lznz / E / Yli - 24 YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO: 23), EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTK (SEQ ID NO: 40), or EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 41), and a variable light chain region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 24). In certain embodiments that may be combined with any of the foregoing embodiments, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L2 binding antagonist is an antibody. In certain modalities that can be combined with any of the preceding modalities, the PD-L2 binding antagonist is an immunoadhesin. In certain modalities which may be combined with any of the preceding modalities, the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, renal cell cancer, colorectal cancer, ovarian cancer, breast, pancreatic cancer, gastric carcinoma, bladder cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer, thyroid cancer, sarcoma, prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphomas, myelomas , mycosis fungoides, Merkel cell cancer, and other hematological diseases. In certain embodiments that can be combined with any of the preceding claims, the agent that decreases or inhibits TIGIT expression and / or activity is administered continuously. In certain embodiments that can be combined with any of the preceding claims, the agent that decreases or inhibits TIGIT expression and / or activity is administered intermittently. In certain embodiments that can be combined with any of the preceding claims, the agent that decreases or inhibits the expression and / or activity of TIGIT is administered before the PD-1 axis binding antagonist. In certain embodiments that may be combined with any of the preceding claims, the agent that decreases or inhibits the expression and / or activity of TIGIT is administered simultaneously with the PD-1 axis binding antagonist. In certain embodiments that can be combined with any of the preceding claims, the agent that decreases or inhibits the expression and / or activity of TIGIT is administered after the PD-1 axis binding antagonist. In certain embodiments that can be combined with any of the preceding claims, the PD-1 axis binding antagonist is administered before the agent that modulates CD226 expression and / or activity. In certain embodiments that may be combined with any of the preceding claims, the PD-1 axis binding antagonist is administered simultaneously with the agent that modulates CD226 expression and / or activity. In certain embodiments that can be combined with any of the preceding claims, the PD-1 axis binding antagonist is administered after the agent that modulates CD226 expression and / or activity. In certain embodiments that can be combined with any of the preceding claims, the agent that decreases or inhibits the expression and / or activity of TIGIT is administered before the agent that decreases or inhibits one or more co-inhibitory hQHQnn / L7R7 / B receptors. / YI - 25 additional immunity. In certain embodiments that may be combined with any of the preceding claims, the agent that decreases or inhibits the expression and / or activity of TIGIT is administered simultaneously with the agent that decreases or inhibits one or more additional receptor co-inhibitors of immunity. . In certain embodiments that may be combined with any of the preceding claims, the agent that decreases or inhibits the expression and / or activity of TIGIT is administered after the agent that decreases or inhibits one or more additional receptor co-inhibitors of immunity. In certain embodiments that may be combined with any of the preceding claims, the agent that decreases or inhibits the expression and / or activity of TIGIT is administered before the agent that increases or activates one or more additional costimulatory immune receptors. In certain embodiments that may be combined with any of the preceding claims, the agent that decreases or inhibits the expression and / or activity of TIGIT is administered simultaneously with the agent that increases or activates one or more additional co-stimulatory receptor immunity. . In certain embodiments that may be combined with any of the preceding claims, the agent that decreases or inhibits the expression and / or activity of TIGIT is administered after the agent that increases or activates one or more additional costimulatory immune receptors. In other aspects, the present disclosure provides a kit comprising a PD-1 spindle-binding antagonist and a package insert comprising instructions for using the PD-1 spindle-binding antagonist in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT to treat or slow the progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity, and a package insert comprising instructions for using the antagonist. PD-1 axis binding agent and agent that decreases or inhibits the expression and / or activity of TIGIT to treat or slow the progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits the expression and / or activity of TIGIT and a package insert comprising instructions for using the agent that decreases or inhibits the expression and / or activity. of TIGIT in combination with a PD-1 axis binding antagonist to treat or slow the progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising a PD-1 spindle-binding antagonist and a package insert comprising instructions for using the PD-1 spindle-binding antagonist in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT to improve the immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity, and a package insert comprising instructions for using the antagonist. PD-1 axis binding agent and the agent that decreases or inhibits the expression and / or activity of TIGIT to improve the immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising an agent that hQHQnn / I 7O7 / E / Yl· - 26 decreases or inhibits TIGIT expression and / or activity and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and / or activity in combination with a PD-axis binding antagonist 1 to improve the immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that modulates the expression and / or the activity of CD226 to treat or slow the progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity, and a package insert comprising instructions for using the binding antagonist. to the PD-1 axis and the agent that modulates the expression and / or activity of CD226 to treat or slow the progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising an agent that modulates CD226 expression and / or activity and a package insert comprising instructions for using the agent that modulates CD226 expression and / or activity in combination. with a PD-1 axis binding antagonist to treat or slow the progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that modulates the expression and / or the activity of CD226 to improve the immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity, and a package insert comprising instructions for using the binding antagonist. to the PD-1 axis and the agent that modulates the expression and / or activity of CD226 to improve the immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising an agent that modulates CD226 expression and / or activity and a package insert comprising instructions for using the agent that modulates CD226 expression and / or activity in combination. with a PD-1 axis binding antagonist to improve the immune function of an individual having cancer. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is an anti-PD-L1 antibody. In certain embodiments that may be combined with any of the preceding embodiments, the anti-PD-L1 antibody is selected from the group consisting of YW243.55.S70, MPDL3280A, MDX-1105, and MEDI4736. In certain embodiments that may be combined with any of the preceding embodiments, the anti-PD-L1 antibody comprises a heavy chain comprising the HVR-H1 sequence from GFTFSDSWIH (SEQ ID NO: 17), the HVR-H2 sequence from AWISPYGGSTYYADSVKG (SEQ ID NO: 18), and the HVR-H3 sequence of RHWPGGFDY (SEQ ID NO: 19); and a light chain comprising the HVR-L1 sequence from RASQDVSTAVA (SEQ ID NO: 20), the HVR-L2 sequence from SASFLYS (SEQ ID NO: 21), and the HVR-L3 sequence from franonn / Lznz / E / YL. - 27 QQYLYHPAT (SEQ ID NO: 22). In certain embodiments that may be combined with any of the preceding embodiments, the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO: 23), EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTK (SEQ ID NO: 40), or EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 41), and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 24). In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is an anti-PD1 antibody. In certain embodiments that may be combined with any of the preceding embodiments, the anti-PD1 antibody is MDX1106, MK-3475, or CT-011. In certain modalities that can be combined with any of the foregoing modalities, the PD-1 axis binding antagonist is AMP-224. In certain embodiments that may be combined with any of the foregoing embodiments, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L2 binding antagonist is an antibody. In certain modalities that can be combined with any of the preceding modalities, the PD-L2 binding antagonist is an immunoadhesin. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits the expression and / or activity of TIGIT and a package insert comprising instructions for using the agent that decreases or inhibits the expression and / or activity. of TIGIT in combination with an agent that decreases or inhibits one or more additional co-inhibitor immune receptors to treat or slow the progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent that decreases or inhibits one or more additional receptor co-inhibitors of immunity, and a package insert. comprising instructions for using the agent that decreases or inhibits the expression and / or activity of TIGIT and the agent that decreases or inhibits one or more additional immune co-inhibitor receptors to treat or slow the progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits one or more co-receptor inhibitors of additional immunity and a package insert comprising instructions for using the agent that decreases or inhibits one or more co-receptors. additional immune inhibitors in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT to treat or slow the progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits the expression and / or activity of TIGIT and a package insert comprising instructions for using the agent hanonn / i zoz / e / yl - 28 that decreases or inhibits the expression and / or activity of TIGIT in combination with an agent that decreases or inhibits one or more additional co-inhibitor immunity receptors to improve the immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent that decreases or inhibits one or more additional receptor co-inhibitors of immunity, and a package insert. comprising instructions for using the agent that decreases or inhibits the expression and / or activity of TIGIT and the agent that decreases or inhibits one or more additional co-inhibitor immune receptors to improve the immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits one or more additional immunity co-inhibitor receptors and a package insert comprising instructions for use of the agent that decreases or inhibits one or more additional co-inhibitor receptors of immunity. additional immunity in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT to improve the immune function of an individual having cancer. In certain modalities that may be combined with any of the preceding modalities, the one or more additional receptor immunity co-inhibitors are selected from the group consisting of PD-1, CTLA-4, LAG3, TIM3, BTLA, VISTA, B7H4, and CD96. In certain modalities that may be combined with any of the preceding modalities, the one or more additional receptor co-inhibitors of immunity are selected from the group consisting of PD-1, CTLA-4, LAG3, and TI M3. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits the expression and / or activity of TIGIT and a package insert comprising instructions for using the agent that decreases or inhibits the expression and / or activity. of TIGIT in combination with an agent that increases or activates one or more additional co-stimulatory immune receptors to treat or slow the progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits TIGIT expression and / or activity and an agent that increases or activates one or more additional costimulatory immune receptors, and a package insert. comprising instructions for using the agent that decreases or inhibits the expression and / or activity of TIGIT and the agent that increases or activates one or more additional costimulatory immune receptors to treat or slow the progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising an agent that increases or activates one or more additional co-stimulatory receptors of immunity and a package insert comprising instructions for using the agent that increases or activates one or more co-receptors. additional immune stimulants in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT to treat or slow the progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits the expression and / or activity of TIGIT and a package insert comprising instructions for using the agent that decreases or inhibits the expression and / or activity. of TIGIT in combination with an agent that increases or activates one or more additional immune co-stimulatory receptors to improve the immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits the expression and / or activity of TIGIT and a - 29 agent that increases or activates one or more additional immune co-stimulatory receptors, and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and / or activity and the agent that increases or activates one or more additional co-stimulatory immune receptors for improving the immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising an agent that increases or activates one or more additional co-stimulatory receptors of immunity and a package insert comprising instructions for using the agent that increases or activates one or more co-receptors. additional immunity stimulators in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT to improve the immune function of an individual having cancer. In certain modalities that may be combined with any of the preceding modalities, the one or more additional immune costimulatory receptors are selected from the group consisting of CD226, OX-40, CD28, CD27, CD137, HVEM, GITR, MICA, ICOS, NKG2D , and 2B4. In certain modalities that may be combined with any of the preceding modalities, the one or more additional costimulatory immune receptors are selected from the group consisting of CD226, OX-40, CD27, CD137, HVEM, and GITR. In certain modalities that may be combined with any of the foregoing modalities, the one or more additional immune co-stimulatory receptors are selected from the group consisting of OX-40 and CD27. In certain modalities that may be combined with any of the preceding modalities, the individual is a human. In certain embodiments that may be combined with any of the preceding modalities, the agent that decreases or inhibits TIGIT expression and / or activity is selected from the group consisting of an antagonist of TIGIT expression and / or activity, an antagonist of PVR expression and / or activity, an agent that inhibits and / or blocks the interaction of TIGIT with PVR, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL2, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL3, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVRL2, and an agent that it inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVRL3. In certain embodiments that may be combined with any of the preceding embodiments, the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody or an antigen-binding fragment thereof. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is an agent that increases and / or stimulates CD226 expression and / or activity. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates the expression and / or activity of CD226 is an agent that increases and / or stimulates the interaction of CD226 with PVR. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates the expression and / or activity of CD226 is an agent that increases and / or stimulates intracellular signaling mediated by the binding of CD226 to PVR. In certain modalities that can be combined with any of the preceding modalities, the agent that modulates the expression and / or activity of CD226 is selected from the group consisting of an agent that inhibits and / or blocks the interaction of CD226 with TIGIT, an antagonist of TIGIT expression and / or activity, an antagonist of hQHQnn / L7R7 / B / YI expression and / or activity - 30 PVR, an agent that inhibits and / or blocks the interaction of TIGIT with PVR, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL2, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL3, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVRL2, and an agent that inhibits and / or blocks signaling intracellular mediated by the binding of TIGIT to PVRL3. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is an agent that inhibits and / or blocks the interaction of CD226 with TIGIT. In certain modalities that can be combined with any of the preceding modalities, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is a small molecule inhibitor, an inhibitory antibody or an antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, or an inhibitory polypeptide. In certain embodiments that may be combined with any of the preceding embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is an anti-TIGIT antibody or an antigen-binding fragment thereof. In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof comprises at least one HVR comprising an amino acid sequence selected from amino acid sequences (1) KSSQSLYYSGVKENLLA (SEQ ID NO: 1), ASIRFT (SEQ ID NO: 2), QQGINNPLT (SEQ ID NO: 3), GFTFSSFTMH (SEQ ID NO: 4), FIRSGSGIVFYADAVRG (SEQ ID NO: 5), and RPLGHNTFDS (SEQ ID NO: 6 ); or (2) RSSQSLVNSYGNTFLS (SEQ ID NO: 7), GISNRFS (SEQ ID NO: 8), LQGTHQPPT (SEQ ID NO: 9), GYSFTGHLMN (SEQ ID NO: 10), LIIPYNGGTSYNQKFKG (SEQ ID NO: 11), and GLRGFYAMDY (SEQ ID NO: 12). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof, wherein the antibody light chain comprises the amino acid sequence described in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO: 13) or DWLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGSGTDFTLKIS TIKPEDLGMYYCLQGTH QPPTFGPGTKLEVK (SEQ ID NO: 14). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof, wherein the antibody heavy chain comprises the amino acid sequence described in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRTISRDNAKNLLF LQMNDLKSEDTAMYYCARRPLGHNTFDS WGQGTLVTVSS (SEQ ID NO: 15 ) either EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLTVDKSSSTA YMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO: 16). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof, wherein the antibody light chain comprises the amino acid sequence described in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO: 13) or DWLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLUFGISNRFSGVPDRFSGSGSGTDFTLKIS hQHQnn / Lznz / E / Yli - 31 TIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO: 14), and the heavy chain of antibodies comprises the amino acid sequence described in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFTISRDNAKNLLF LQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO: 15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLTVDKSSSTA YMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO: 16). BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1D show that TIGIT is highly expressed on depleted CD8+ and CD4+ T cells. Figure 1A depicts MACS-enriched C57BL6 / J splenic CD8+ T cells that were stimulated with plate-bound anti-CD23 and anti-CD28 for 24 to 48 hours in vitro. Flow cytometry histograms represent TIGIT expression (red) relative to isotype staining (grey). Also shown is MFI quantification of TIGIT***, P < 0.001. Data are representative of 2 independent experiments; n=3. In Figures 1B and 1C, C57BL6 / J mice were infected with Armstrong-stained LCMV and splenocytes were analyzed 7 days post-infection. Data are representative of 2 independent experiments; n=5. Figure 1B shows representative flow cytometry histogram of TIGIT expression by naive CD4+ and CD8+ T cells (CD44ba¡°CD62Lalt°) and effector memory (CD44alt0CD62Lba¡°). TIGIT MFI quantification is also shown. ***, P < 0.001. Figure 1C shows representative flow cytometry histogram of TIGIT expression by PD-1alt0 and PD-1ba¡° effector memory CD8+ T cells. TIGIT MFI quantification is also shown. ***, P < 0.001. Figure 1D shows that C57BL6 / J mice were briefly depleted of CD4+ T cells and infected with LCMV strain Clone 14. Splenocytes were analyzed 42 days post infection. The flow cytometry histogram represents TIGIT expression by naive (CD44ba¡°CD62Lalt0), central memory (CD44alt0CD62Lalt0) and effector memory (CD44alt0CD62Lba¡0) CD8+ T cells. TIGIT MFI quantification is also shown. ***, P < 0.001. Data are representative of 2 independent experiments; n = 5. Error bars represent the standard error of the mean. Figure 2 shows the design of TIGITloxP / loxP mice. TIGIT exon 1 was flanked by loxP sites using standard techniques. Figures 3A-3D show that TIGIT-deficient CD8+ and CD4+ T cells respond normally to acute viral infection. Littermates TIGIT™1CD4cre(CKO) and TIGIT™ (WT) were infected with LCMV strain Armstrong. Splenocytes were analyzed 7 days after infection. Data are representative of two independent experiments; n = 5. Figure 3A shows representative FACS plots introduced into CD8+ T cells, with activated (CD44alt0) cells enclosed. Quantification of activated CD8+ T cells as a percentage of total CD8+ T cells. Figure 3B shows representative FACS plots introduced into CD8+ T cells after in vitro stimulation, with the IFNγ-producing cells locked in. Quantification of IFNy-producing cells as a percentage of total CD8+ T cells. Figure 3C shows - 32 representative FACS plots inserted into CD4+ T cells, with the activated cells (CD44alt0) locked. Quantification of activated CD4+ T cells as a percentage of total CD4+ T cells. Figure 3D shows representative FACS plots introduced into CD4+ T cells after in vitro stimulation, with the IFNγ-producing cells locked in. Quantification of IFNy-producing cells as a percentage of total CD4+ T cells. The error bars represent the standard error of the mean. Figures 4A-4H show that TIGIT and PD-1 synergistically regulate the effector function of depleted T cells in vivo. In Figures 4A to 4E, TIGITfl / flCD4-cre- (WT) and TIGITfl / flCD4-cre+ (CKO) mice were briefly depleted of CD4+ T cells and infected with LCMV strain Clone 13. Splenocytes and viral titers from the liver were analyzed 42 days after infection. Data are representative of 2 independent experiments, and from n = 6 to 9 per group. Figure 4A depicts representative FACS plots introduced into CD8+ T cells, with the activated cells (CD44alt° CD62Lba¡°) locked up. Quantification of activated cells as a percentage of total CD8+ T cells. Figure 4B depicts representative FACS plots introduced into CD8+ T cells after in vitro stimulation, with IFNγ+ cells locked in. Quantification of IFNy-producing cells as a percentage of CD8+ T cells. Figure 4C depicts representative FACS plots introduced into CD4+ T cells, with the activated cells (CD44alt0CD62Lba¡°) locked away. Quantification of activated cells as a percentage of total CD4+ T cells. Figure 4D depicts representative FACS plots introduced into CD4+ T cells after in vitro stimulation, with the IFNγ cells gated. Quantification of IFNy-producing cells as a percentage of CD4+ T cells. Figure 4E represents the quantification of LCMV titers in the liver. ***, P < 0.0001. In Figure 4F to 4H, C57BL6 / J mice were briefly depleted of CD4+ T cells and infected with LCMV strain Clone 13. Mice were treated with isotype-matched control, anti-PD-L1, anti-TIGIT antibodies. , or anti-PD-L1 + anti-TIGIT beginning 28 days after infection. Splenocytes and liver viral titers were analyzed 42 days post infection. Data are representative of 2 independent experiments; n=10. Figure 4F depicts representative FACS plots introduced into CD8+ T cells, with the activated cells (CD44all°CD62Lbai°) enclosed. Quantification of activated cells as a percentage of total CD8+ T cells. ***, P < 0.0001. Figure 4G depicts representative FACS plots introduced into activated CD8+ T cells after in vitro stimulation, with the IFNγ cells gated. Quantification of IFNy-producing cells as a percentage of activated CD8+ T cells. *. P = 0.0352. **, P = 0.0047. Figure 4H represents the quantification of LCMV titers in the liver. *, P = 0.0106. **, P = 0.0047. The error bars represent the standard error of the mean. Figures 5A-5B show that TIGIT / PD-L1 co-blockade enhances CD4+ T cell effector function during chronic viral infection. C57BL6 / J mice were depleted of CD4+ T cells and infected with LCMV strain Clone 13. Mice were treated with isotype control, anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT from 28 days after infection. Splenocytes and liver viral titers were analyzed 42 days post infection. Data are representative of 2 independent experiments; n = 10. Figure 5A represents representative FACS diagrams introduced into CD4+ T cells, with the cells activated (CD44alt0hQDQnn / I 7O7 / E / Yl· - 33 CD62Lba¡0) enclosed. Quantification of activated CD4+ T cells as a percentage of total CD4+ T cells. Figure 5B depicts representative FACS plots introduced into CD4+ T cells after in vitro stimulation, with the IFNγ-producing cells locked in. Quantification of IFNy-producing cells as a percentage of total CD4+ T cells. *, P = 0.019. The error bars represent the standard error of the mean. Figures 6A-6D show that TIGIT expression is elevated in human breast cancer and correlates with expression of CD8 and inhibitory co-receptors. Microarray data of breast cancer gene expression were analyzed using the Cancer Gene Atlas NetWork. Gene expression data were normalized and expressed as relative proportions (Iog2). Figure 6A depicts TIGIT expression in normal and all breast tumor samples (left) and in breast tumor subtypes (right). ***, P = 6x1012. Boxplots are shown. Figure 6B represents the correlation of the expression of TIGIT and CD3s. R2 = 0.61. Figure 6C depicts the correlation of TIGIT and CD8o (left, R2 = 0.80) or CD4 (right, R2 = 0.42). Figure 6D depicts the correlation of TIGIT and PD-1 (left, R2 = 0.87), LAG3 (middle, R2 = 0.80), and CTLA4 (right, R2 = 0.76). Figures 7A-7F show that TIGIT and PD-1 inhibit T cell anti-tumor responses. In Figures 7A-7B, BALB / C mice were inoculated with CT26 colorectal carcinoma cells. Splenocytes and tumor-infiltrating lymphocytes (TlLs) were analyzed 14 post-inoculation, when tumors had reached a size of approximately 200 mm3. Data are representative of one experiment; n=6. Figure 7A depicts representative flow cytometry histogram of TIGIT expression by splenic and tumor infiltrating CD8+ T cells. TIGIT MFI quantification is also shown. **, P = 0.0023. Figure 7B depicts representative flow cytometry histogram of TIGIT expression by splenic and tumor infiltrating CD4+ T cells. TIGIT MFI quantification is also shown. ***, P = 0.0002. In Figure 7C to 7E, BALB / C mice were inoculated with CT26 colorectal carcinoma cells. When tumors reached a size of approximately 200 mm3, mice were treated with isotype control, anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT antibodies for three weeks. Data are representative of two independent experiments; n = 10-20 (Figure 7C to 7D) or 7-10 (Figure 7E). Figure 7C depicts the average CT26 tumor volumes over time. Figure 7D depicts mouse survival. Figure 7E shows that approximately 60 days after the initial inoculation, mice in complete remission (CR) that had received anti-TIGIT + anti-PD-L1, as well as naive BALB / c mice, were inoculated with CT26 cells in the left thoracic flanks and inoculated with EMT6 breast carcinoma cells into their breast adipose tissues. Mean (left) and individual (right) tumor volumes for CT26 (squares) and EMT6 (triangles) in CR mice (purple and green) and tumors in naive mice (black and orange) are shown. Figure 7F shows that mice were inoculated with CT26 tumors and treated as in Figure 7C. Tumor-infiltrating and tumor-draining lymph node-resident T cells were analyzed by flow cytometry. Representative FACS plots of CD8+ TlLs after in vitro stimulation, with IFNγ-producing cells locked in. Quantification of IFNy-producing CD8+ TlLs as a percentage of total CD8+ TlLs. ***, P = hanonn / i zoz / e / yl -34 0.0003. Data are representative of two independent experiments; n = 5. Error bars represent the standard error of the mean. Figures 8A-8B show that TIGIT expression in CT26 tumor-infiltrating lymphocytes correlates with Tim-3 expression. BALB / C mice were inoculated with CT26 colorectal carcinoma cells. Splenocytes and tumor-infiltrating lymphocytes (TlLs) were analyzed approximately 14 days post-inoculation, when tumors had reached a size of approximately 200 mm3. Data are representative of one experiment; n=6. Figure 8A depicts a representative histogram of TIGIT expression by splenic and tumor infiltrating CD8+ T cells. TIGIT MFI quantification. **, P = 0.0026. Figure 8B depicts a representative histogram of TIGIT expression by splenic and tumor infiltrating CD4+ T cells. TIGIT MFI quantification. ***, P < 0.0001. The error bars represent the standard error of the mean. Figures 9A-9B show that the expression of TIGIT in MC38 tumor-infiltrating lymphocytes correlates with the expression of PD-1 and Tim-3. C57BL6 / J mice were inoculated with MC38 colorectal carcinoma cells. Splenocytes and tumor-infiltrating lymphocytes (TlLs) were analyzed approximately 14 days post-inoculation, when tumors had reached a size of approximately 200 mm3. Data are representative of one experiment; n=5. Figure 9A depicts a representative histogram of TIGIT expression by splenic and tumor infiltrating CD8+ T cells. TIGIT MFI quantification. ***, P < 0.0001. Figure 9B depicts a representative histogram of TIGIT expression by splenic and tumor infiltrating CD4+ T cells. TIGIT MFI quantification. *, P = 0.0136. **, P = 0.0029. The error bars represent the standard error of the mean. Figure 10 shows the growth of the CT26 tumor in mice treated with anti-PD-L1 and / or anti-TIGIT. Naif BALB / C mice were inoculated with CT26 tumor cells and treated with anti-PD-L1 and / or anti-TIGIT or isotype-matched control antibodies, as described in Figures 4D to 4F. Tumor volumes over time for individual mice in each treatment group are shown. Data are representative of two independent experiments. Figures 11A-11F show flow cytometric analysis of CD4+ TlLs and lymph node T cells draining the tumor. BALB / C mice were inoculated with CT26 colorectal carcinoma cells. When tumors reached a size of approximately 200 mm3, mice were treated with isotype control, anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT for 7 days. Tumors and lymph nodes draining the tumor were harvested. Data are representative of two independent experiments; n=5. Representative FACS plots inserted into tumor-draining lymph node CD8+ T cells after in vitro stimulation, with IFNγ-producing cells locked in. IFNy+ cell quantification as a percentage of total CD8+ T cells. ***, P < 0.001. Quantification of CD8+ T cells as a percentage of total TlLs. **, P = 0.0065. Quantification of activated CD8+ T cells (CD44alt0CD62Lba'°) as a percentage of total CD8+ TlLs. *, P = 0.012. Quantification of CD8+ T cells as a percentage of total hanonn / i zoz / e / yl cells - 35 lymph nodes that drain the tumor. Quantification of activated CD8+ T cells as a percentage of total CD8+ T cells in the lymph node draining the tumor. *, P < 0.05. Figure 11C depicts the quantification of CD4+ T cells as a percentage of total TlLs. *, P = 0.016. Figure 11D depicts the quantification of activated CD4+ T cells as a percentage of total CD4+ TlLs. Figure 11E depicts the quantification of CD4+ T cells as a percentage of the total lymph node cells draining the tumor. Figure 11F depicts the quantification of activated CD4+ T cells as a percentage of total CD4+ T cells in the lymph node draining the tumor. Figure 11A depicts the quantification of IFNy+ cells as a percentage of CD4+ TlLs after in vitro stimulation. Figure 11B depicts the quantification of ΙΡΝγ+ cells as a percentage of CD4+ T cells in the tumor-draining lymph node after in vitro stimulation. The error bars represent the standard error of the mean. Figure 12A-12C further shows flow cytometric analysis of CD8+ TlLs. BALB / C mice were inoculated with CT26 colorectal carcinoma cells and treated with isotype control, anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT antibodies as described in Figures 4A-4H. Tumors were harvested after 7 days of treatment and analyzed by flow cytometry. Data are representative of two independent experiments; n=5. Figure 12A depicts the quantification of TNFo+ cells as a percentage of total CD8+ TlLs. **, P < 0.01. Figure 12B depicts the quantification of CD8+ TlLs as a percentage of total TlLs. **, P < 0.01. Figure 12C depicts the quantification of activated CD8+ TlLs (CD44alt° CD62Lba¡°) as a percentage of total CD8+ TlLs. *, P < 0.05. The error bars represent the standard error of the mean. Figures 13A-13D show flow cytometric analysis of tumor-draining lymph node resident CD8+ T cells. BALB / C mice were inoculated with CT26 colorectal carcinoma cells and treated with isotype control, anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT antibodies as described in Figure 4A-4H. . Lymph nodes draining the tumor were harvested after 7 days of treatment and analyzed by flow cytometry. Data are representative of two independent experiments; n=5. Figure 13A depicts representative FACS plots introduced into tumor-draining lymph node-resident CD8+ T cells after in vitro stimulation, with the IFNγ-producing cells enclosed. Quantification of ΙΡΝγ+ cells as a percentage of total CD8+ T cells. ***, P < 0.001. Figure 13B represents the quantification of CD8+ T cells as a percentage of the total cells in the lymph node draining the tumor. Figure 13C depicts the quantification of activated CD8+ T cells (CD44alt0CD62Lba¡°) as a percentage of total CD8+ T cells. *, P < 0.05. The error bars represent the standard error of the mean. Figure 13D depicts the quantification of TNFα-producing cells as a percentage of the total lymph node CD8+ T cells draining the tumor. Figure 14 shows the co-expression of CD226 and TIGIT by tumor infiltrating CD8+ T cells. C57BL6 / J mice were inoculated with MC38 colorectal carcinoma cells. Splenocytes and tumor-infiltrating lymphocytes (TlLs) were analyzed approximately 14 days post-inoculation, when tumors had reached a size of approximately 200 mm3. Representative histogram of the expression of - 36 CD226 by splenic B cells (grey), splenic CD8+ T cells (blue), and tumor-infiltrating CD8+ TIGIT+ T cells (red). Data are representative of two independent experiments; n=5. Figure 15 shows a co-immunoprecipitate (co-IP) of CD226 and TIGIT in transfected cells. COS7 cells were co-transfected with expression plasmids containing the cDNA for either TIGIT-HA (5 ng) or CD226-Flag (10 ng) tagged proteins, or a control plasmid (pRK). After transfection, the cells were washed and spun down and the cell pellets lysed. The resulting supernatant was pre-purged and centrifuged and then divided equally between two tubes and immunoprecipitated with either anti-HA or anti-flag using standard procedures. The immunoprecipitated proteins were subjected to SDS-PAGE and western immunoassays. Western immunoassays were tested with either anti-Flag-HRP or anti-HA-HRP. Figure 16 shows that TIGIT and CD226 interact on primary CD8+ T cells. MACS-enriched C57BL6 / J splenic CD8+ T cells were stimulated with plaque-bound anti-CD3 and anti-CD28 antibodies and recombinant IL-2 for 48 hours and lysed. Cellular cells were immunoprecipitated with anti-TIGIT and probed with anti-CD226. Lines: molecular weight scale (1), input (2), co-immunoprecipitation flow path (3), and co-immunoprecipitate. The arrow denotes the expected molecular weight of CD226. Figure 17A-17D shows the detection of the TIGIT / CD226 interaction by means of TR-FRET. Figure 17A depicts the cleavage of Flag-ST-CD226 homodimers by means of HA-TIGIT. FRET ratio between Flag-ST-CD226 measured on COS-7 cells expressing a constant amount of Flag-ST-CD226 and increasing concentrations of HA-TIGIT. Figure 17B depicts the FRET ratio between Flag-ST-CD226 recorded after a 15 minute incubation of either PBS (white bar) or anti-TIGIT antibody (black bar). Figure 17C depicts the association of Flag-ST-CD226 with HA-TIGIT. FRET intensity between Flag-STCD226 and HA-TIGIT on the expression of Flag-ST-CD226 measured by means of an anti-Flag ELISA on the same batch of transfected COS-7 cells. Figure 17D depicts the FRET variation between Flag-ST-CD226 and HA-TIGIT after a 15 minute incubation of PBS (white bar) or anti-TIGIT antibody (black bar). Data in A and C are representative of 4 independent experiments, each carried out in triplicate. Data in B and D are representative of 2 independent experiments, each carried out in triplicate. Figure 18 shows the cell surface expression of Flag-ST-CD226 and HA-TIGIT. antiFlag and anti-HA ELISA on intact COS-7 cells expressing the indicated tagged constructs. Data are representative of 3 independent experiments, each carried out in triplicate. Figures 19A-19D show that blocking CD226 reverses the enhanced anti-viral T cell response induced by TIGIT / PD-L1 co-blocking. In Figures 19A to 19D, C57BL6 / J mice were briefly depleted of CD4+ T cells and infected with LCMV strain Clone 13. Mice were treated with isotype-matched control, anti-CD226, anti-PD-L1 + anti -TIGIT, or anti-PD-L1 + anti-TIGIT + anti-CD226 beginning 28 days after infection. Splenocytes and liver viral titers were analyzed 42 days after infection. Figure 19A depicts the quantification of CD8+ T cells as a percentage of splenocytes. Figure 19B depicts the quantification of activated CD8+ T cells as a percentage of total hQHQnn / I 7O7 / E / Yl T cells. - 37 CD8+. ***, Ρ < 0.001. Figure 19C depicts the quantification of IFNγ-producing cells as a percentage of activated CD8+ T cells. ***, P < 0.001. Figure 19D depicts the quantification of liver LCMV titers. ***, P < 0.001. The error bars represent the standard error of the mean. Figures 20A-20H show that TIGIT expression is elevated in human cancer and strongly correlates with CD8 and PD-1. Gene expression analyzes of human cancers were performed as described in Example 11. Scatterplots show count data per gene, normalized by library size. Boxplots show the ratio of the stabilized variation expression of TIGIT and CD3e. Figure 20A depicts the correlation of TIGIT and CD3e RNA expression in LUSC (grey) and normal lung (black), p = 0.86. Quantification of TIGIT / CD3e expression ratios is also shown. Increased proportion of LUSC = 372%. ***, P = 1.46 x 10-46. Figure 20B depicts the correlation of TIGIT and CD3e RNA expression in COAD (grey) and normal (black) colon, p = 0.83. Quantification of TIGIT / CD3e expression ratios is also shown. COAD ratio increase = 116%. ***, P = 3.66 x 10-6. Figure 20C depicts the correlation of TIGIT and CD3e RNA expression in UCEO (grey) and normal uterine endometrium (black), p = 0.87. Quantification of TIGIT / CD3e expression ratios is also shown. Increase in the proportion of UCEC = 419%. ***, P = 7.41 x 10-5. Figure 20D depicts the correlation of TIGIT and CD3e RNA expression in BRCA (grey) and normal breast (black), p = 0.82. Quantification of TIGIT / CD3e expression ratios is also shown. Increased BRCA ratio = 313%. ***, P = 4.6 x 10-44. Figure 20E depicts the correlation of TIGIT and CD3e RNA expression in clean renal cell kidney carcinoma (grey) and normal kidney (black), p = 0.94. Quantification of TIGIT / CD3e expression ratios is also shown. Figure 20F depicts the correlation of TIGIT and CD8A (left) or TIGIT and CD4 (right) in squamous cell lung carcinoma (grey) and normal lung (black), p = 0.77 and 0.48 respectively. Figure 20G depicts the correlation of TIGIT and PD-1 (Pdcdl) in squamous cell lung carcinoma (grey) and normal lung (black), p = 0.82. Figure 20H depicts the correlation of TIGIT and CD226 in squamous cell lung carcinoma (red) and normal lung (black), p = 0.64. Figure 21 shows analysis of T cell-associated gene expression in lung squamous cell carcinoma (LUSC). Gene expression in LUSC and normal tissue samples was analyzed as described in Example 11 and a heat map of genes best correlated with gene signature in LUSC samples was generated. Genes and samples were clustered using hierarchical clustering using the Ward link in the Euclidean distance matrix for centered and scaled expression data. Figures 22A-22G show that TIGIT and PD-1 are expressed in a coordinated manner by tumor-infiltrating human and murine lymphocytes. Figures 22A-22C show analysis of lymphocytes from a freshly excised human NSCLC tumor, tumor-matched peripheral blood, and normal donor peripheral blood. Data are representative of two tumors analyzed independently. Figure 22A depicts representative FACS plots depicting TIGIT expression by peripheral and tumor-infiltrating CD8+ T cells, with TIGIT+ cells enclosed. Figure 22B depicts representative FACS diagrams - 38 depicting TIGIT expression by peripheral and tumor-infiltrating CD4+ T cells, with TIGIT+ cells enclosed. Figure 22C depicts a flow cytometry histogram depicting TIGIT expression by means of PD-1alt0 (red) and PD-1ba¡° (blue) CD8+ (left) and CD4+ (right) T cells infiltrating NSCLC. In Figures 22D to 22G, BALB / C mice were inoculated with syngeneic CT26 colorectal cancer cells. Splenocytes and tumor infiltrating lymphocytes (TlLs) were analyzed 14 days after inoculation, when the tumors had reached a size of approximately 200 mm3. Data are representative of two independent experiments; n=5-6. Figure 22D depicts a representative FACS plot of TIGIT expression by tumor infiltrating CD8+ T cells, with TIGIT+ cells enclosed. Figure 22E depicts a representative FACS plot of TIGIT expression by tumor-infiltrating CD4+ T cells, with TIGIT+ cells enclosed. Quantification of TIGIT+ T cell frequency as a percentage of all T cells. *, P = 0.0134. ***, P < 0.0001. Figure 22F depicts a flow cytometry histogram depicting TIGIT expression by tumor-infiltrating CD8+ PD-1alt° and PD-1ba¡° T cells and by splenic CD8+ T cells. TIGIT MFI quantification is also shown. **, P = 0.0023. Figure 22G depicts a flow cytometry histogram depicting TIGIT expression by tumor-infiltrating CD4+ PD1a|tQ and PD-1ba¡° T cells and by splenic CD4+ T cells. TIGIT MFI quantification is also shown. ***, P = 0.0002. The error bars represent the standard error of the mean. Figures 23A-23D show characterization of TIGIT expression by tumor infiltrating human T cells. Figures 23A to 23B depict FACS plots showing TIGIT expression by tumor-infiltrating CD8+ NSCLC and CD4+ T cells (Figure 23A) and by donor-matched CD8+ PBMC and CD4+ T cells (Figure 23B). with TIGIT+ cells enclosed. Figures 23C to 23D depict FACS diagrams showing TIGIT expression by tumor-infiltrating CD8+ CRC and CD4+ T cells (Figure 23C) and by donor-matched CD8+ PBMC and CD4+ T cells (Figure 23D). with the TIGIT+ cells enclosed. Figure 24 shows that the TIGIT:CD226 interaction is not driven by PVR TIGIT:CD226 and TIGIT Q56R:CD226 interactions were detected by TR-FRET and the FRET ratio between Flag-ST-CD226 and HA- TIGIT or HA-TIGIT Q56R shows that TIGIT WT and Q56R bind to CD226 with the same efficiency. Data are representative of three independent experiments carried out in triplicate. Figures 25A-25C show the efficacy of co-blocking the TIGIT / PD-L1 antibody in MC38-bearing mice. In Figures 25A to 25C, MC38 tumor-bearing mice were generated as above and treated with blocking antibodies against PD-L1 (red), TIGIT (blue), TIGIT and PD-L1 (purple) or control antibodies. matched to the isotype (black) for three weeks. N = 10 (control, anti-PD-L1 alone, anti-TIGIT alone) or 20 (antiTIGIT + anti-PD-L1). Figure 25A depicts average (left) and individual (right) MC38 tumor volumes over time. Figure 25B depicts MC38 tumor volumes after 14 days of antibody treatment. ***, P = 0.0005. **, P = 0.0093. *, P = 0.0433. Figure 25C depicts mouse survival over time. The error bars represent the standard error of the mean. hQHQnn / I 7O7 / E / Yl· - 39 Figure 26A-26E further shows characterization of TIGIT expression by tumor infiltrating murine T cells. Figure 26A depicts that C57BL6 / J splenic CD8+ T cells were spiked for MACS and plated with agonist anti-CD3 and anti-CD28 antibodies. Representative histograms of TIGIT staining (red) and isotype-matched control (solid gray) over time. TIGIT MFI quantification. ***, P < 0.001. Stimulated cells inducibly expressed PD-1 and constitutively expressed CD226 (data not shown). Data are representative of two independent experiments; n=5. In Figures 26B to 26E, wild-type C57BL6 / J mice were inoculated subcutaneously with syngeneic MC38 colorectal carcinoma cells. Tumors were allowed to grow without intervention until they reached a size of 150 to 200 mm3. Data are representative of two independent experiments; n=5. Figure 26B depicts a representative FACS plot of tumor-infiltrating CD8+ T cells, with TIGIT+ cells enclosed. Quantification of the frequency of TIGIT+ cells as a percentage of all tumor-infiltrating or splenic CD8+ T cells. ***, P < 0.0001. Figure 26C depicts a representative FACS diagram of tumor infiltrating CD4+ T cells, with TIGIT+ cells enclosed. Quantification of the frequency of TIGIT+ cells as a percentage of all tumor-infiltrating or splenic CD4+ T cells. ***, P < 0.0001. Figure 26D depicts a representative histogram of TIGIT expression by tumor-infiltrating CD8+ PD-1alt0 and PD-1ba¡° T cells (red and blue, respectively) and by splenic CD8+ T cells (grey). TIGIT MFI quantification. ***, P < 0.0001. Figure 26E depicts a representative histogram of TIGIT expression by tumor-infiltrating CD4+ PD-1alt0 and PD-1ba¡° T cells and by splenic CD4+ T cells. TIGIT MFI quantification. *, P = 0.0136. **, P = 0.0029. The error bars represent the standard error of the mean. Figures 27A-27B show that tumor-infiltrating CD8+ and CD4+ T cells maintain a high level of expression of CD226. Wild-type BALB / C mice were inoculated with CT26 tumor cells as described herein. After the tumors had grown to a size of approximately 150 to 200 mm3, the tumors and spleens were analyzed by flow cytometry. Figure 27A depicts the quantification of CD8+ CD226+ T cells, CD4+ T cells, and non-T cells, as a percentage of all CD8+ T cells, CD4+ T cells, and non-T cells, respectively. Figure 27B depicts representative histograms of CD226 expression in tumor and spleen. Data are representative of two independent experiments; n = 5. Error bars represent the standard error of the mean. Figures 28A-28F show that TIGIT suppression of CD8+ T cell responses is dependent on CD226. BALB / C mice were inoculated subcutaneously with CT26 colorectal carcinoma cells in their right thoracic flanks. When the tumors reached a size of approximately 200 mm3, the mice were treated with isotype control (black), anti-CD226 (orange), anti-PD-L1 (red), anti-TIGIT + anti-PD-L1 ( purple), or anti-TIGIT + anti-PD-L1 + anti-CD226 (green) for three weeks. Data are representative of one experiment; n = 10 (A-B) or 5 (C-F). Figure 28A depicts average (left) and individual (right) CT26 tumor volumes over time. Figure 28B depicts mouse survival over time. In the - 40 Figures 28C to 28F, after 7 days of treatment, tumor-infiltrating lymphocytes and tumor-draining lymph node-resident lymphocytes were evaluated by flow cytometry. Figure 28C depicts the quantification of IFNγ-producing CD8+ TILs as a percentage of total CD8+ TILs after in vitro stimulation. **, P < 0.01. Figure 28D depicts the quantification of IFNγ-producing cells as a percentage of total CD8+ T cells after in vitro stimulation. *, P < 0.05. Figure 28E depicts the quantification of CD8+ TlLs as a percentage of total TlLs. **, P < 0.01. Figure 28F depicts the quantification of CD8+ T cells as a percentage of all tumor-draining lymph node-resident lymphocytes. The error bars represent the standard error of the mean. Figures 29A-29H show that TIGIT affects CD226 function by directly disrupting CD226 homodimerization. Figure 29A depicts that CD8+ T cells were enriched with MACS from CD4cre TIGIT™ (CKO) and CD4wt TIGIT™ (WT) littermates and stimulated in the presence of anti-CD226 antibodies or isotype-matched control as indicated. H3-thymidine uptake is shown as a ratio of cells cultured with anti-CD3 + PVR-Fc to cells cultured with anti-CD3 alone. **, P = 0.0061. ***, P < 0.0001. Data are representative of two independent experiments; n=5. Figure 29B depicts that wild-type C57BL6 / J CD8+ T cells were spiked with MACS and stimulated in the presence of anti-TIGIT, anti-CD226, and / or isotype-matched control antibodies as indicated. H3-thymidine uptake is shown as a ratio of cells cultured with anti-CD3 + PVR-Fc to cells cultured with anti-CD3 alone. ***, P < 0.001 in paired t-tests. Figure 29C depicts that primary human CD8+ T cells were spiked with MACS from blood and stimulated with sub-optimal levels of plaque-bound anti-CD3 in the presence or absence of recombinant human PVR-Fc. Anti-TIGIT antibodies or isotype matched control were added as indicated. Quantification of 3H-thymidine uptake. **, P = 0.0071 and 0.0014 respectively. Figure 29D depicts that CHO cells were transiently transfected with increased concentrations of acceptor and donor FLAG-STCD226, as indicated. Quantification of FRET intensity relative to donor emission. The data are representative of three independent experiments; n=3. In Figures 29E to 29F, CHO cells were transiently transfected with FLAG-ST-CD226 and with increased concentrations of HA-TIGIT, as indicated. Data are representative of two or more independent experiments; n = 4. Data were normalized to the maximum signal. Figure 29E depicts the quantification of the CD226:CD226 FRET ratio (FRET ratio 1). Figure 29F depicts the quantification of the FRET ratio of TIGIT:CD226 (FRET ratio 2). Figure 29G depicts anti-FLAG (left) and anti-HA (right) immunoassays carried out on either anti-FLAG or anti-HA immunoprecipitates prepared from COS-7 cells transfected with either an empty pRK vector or a pRK vector. combination of Flag-CD226 and HA-TIGIT. Data are representative of two independent experiments. Figure 29H depicts the quantification of the TIGIT:CD226 FRET ratio after incubation with PBS (white) or anti-TIGIT antibodies (red). ***, P < 0.001. Data are representative of 4 independent experiments; n = 3. Error bars represent the standard error of the mean. Figure 30 shows that human primary T cells were spiked with MACS from franonn / Lznz / E / YL. - 41 of blood and stimulated with anti-CD3 and anti-CD28. TIGIT+ and TIGIT- cells were sorted, rested, restimulated, and FRET-labeled with the indicated antibodies. Data are representative of two independent experiments. ***, P < 0.001. The error bars represent the standard error of the mean. Figures 31A-31C show that co-blocking TIGIT and PD-1 does not restore effector function of depleted CD4+ T cells during chronic viral infection. Figure 31A depicts the quantification of CD8+ T cells as a percentage of all splenocytes. Figure 31B depicts the quantification of Pentamer+ GP33 cells as a percentage of all splenic CD8+ T cells. **, P = 0.0040. Figure 31C depicts representative FACS plots introduced into gp33 pentamer+ CD8+ T cells after in vitro stimulation, with IFNγ+ cells gated. Quantification of IFNy-producing cells as a percentage of all CD8+ pentamer+ gp33 T cells. *, P = 0.0319. **, P = 0.0030. The error bars represent the standard error of the mean. Figures 32A-32C show that the efficacy of TIGIT / PD-L1 co-blocking is dependent on CD8+ T cells. In Figures 32A to 32B, wild-type BALB / C mice were inoculated with CT26 tumors as described in Figures 7A-7F. When the tumors reached a size of 100 to 150 mm3, the mice were temporarily depleted of CD8+ T cells and treated with anti-TIGIT + anti-PD-L1. Data are representative of one experiment; n = 10 / group. Figure 32A depicts average (left) and individual (right) CT26 tumor volumes over time. Figure 32B represents the quantification of CT26 tumor volumes 17 days after starting treatment. ***, P = 0.0004. In Figure 32C, wild-type BALB / C mice were inoculated with CT26 tumors and treated with anti-TIGIT + anti-PD-L1 and subsequently challenged again with CT26 tumors with temporary depletion of CD8+ T cells at time of delivery. test yourself again. Data are representative of two independent experiments; n=5. Figure 32C depicts mean (left) and individual (right) CT26 tumor volumes over time. The error bars represent the standard error of the mean. Figure 33 shows that PVR expression in tumor cells is essential for co-blocking TIGIT / PD-L1 efficacy. Wild-type BALB / C mice were inoculated with wild-type or PVR-deficient (PVR.KO) tumors as described. When tumors reached a size of 150 to 200 mm3, mice were treated with anti-TIGIT + anti-PD-L1 antibodies or isotype-matched control. Data are representative of one experiment; n = 10 / group. Figure 33 depicts the mean (left) and individual (right) CT26 tumor volumes over time. Figure 34 shows the co-blocking efficacy of the TIGIT / PD-L1 antibody in mice bearing EMT6 tumors. EMT6 tumor-bearing mice were generated as above and treated with blocking antibodies against PD-L1 (red), TIGIT (blue), TIGIT and PD-L1 (purple) or isotype-matched control (black) for three weeks. N = 10 (control, anti-PD-L1 alone, anti-TIGIT alone) or 20 (anti-TIGIT + anti-PD-L1). Figure 34 depicts mean (left) and individual (right) EMT6 tumor volumes over time. Figures 35A-35B show that TIGIT regulates effector function of the tumor-infiltrating CD8+ T cell. BALB / C mice were inoculated subcutaneously with CT26 colorectal carcinoma cells in their hQHQnn / I 7O7 / E / Yl - 42 right thoracic flanks and treated with anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT, as described in Figure 7A-7F. Tumor-draining and tumor-infiltrating lymph node-resident T cells (dLN) were analyzed by flow cytometry 7 days after initiation of treatment. Data are representative of two independent experiments; n=5. Figure 35A depicts the quantification of dLN-resident CD8+ and CD4+ T cells producing double IFNγ / TNFo as percentages of total dLN-resident CD8+ and CD4+ T cells respectively. Dual cytokine production by unstimulated T cells is also shown. **, P = 0.002, 0.003, and 0.001 respectively. Figure 35B depicts the quantification of IFNγ / TNFo dual-producing tumor-infiltrating CD8+ and CD4+ T cells as percentages of total tumor-infiltrating CD8+ and CD4+ T cells respectively. Dual cytokine production by unstimulated T cells is also shown. ***, P < 0.0001. The error bars represent the standard error of the mean. Figures 36A-36B show analysis of lymphocytes from excised human NSCLC tumors, tumor-matched peripheral blood, and normal donor peripheral blood. Data is pooled from three independently acquired sample sets. Figure 36A depicts the quantification of TIGIT+ cells as a percentage of all CD8+ T cells. *, P < 0.05. Figure 36B depicts the quantification of TIGIT+ cells as a percentage of all CD4+ T cells. Figure 37A-37B shows the characterization of TIGIT expression in human tumors. Figure 37A depicts a representative histogram of flow cytometry of TIGIT expression by tumor-resident lymphocytes NSCLC (red, CD45+ FSCba¡°), myeloid cells (blue, CD45+ FSCalt°), and non-hematopoietic cells ( green, CD45-) relative to isotype-matched subset staining (grey). Figure 37B depicts the introduction strategy for CD8+ and CD4+ PD-1alto and PD-1ba¡° T cells infiltrating the NSCLC tumor. DETAILED DESCRIPTION OF THE INVENTION I. General Techniques The techniques and procedures described or referred to herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely used methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual. Molecular Cloning: A Laboratory Manual 3rd Edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003)); Methods in Enzymology series (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames, and G.R. Tayloreds. (1995)), Harlowy Lane, eds. . (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.l. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (Animal Cell Culture) (R.l. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (Culture in hQHQnn / I 7O7 / E / Yl· - 43 Cells and Tissue: Laboratory Procedures) (A. Doyle, J.B. Griffiths, & D.G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D.M. Weiry C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction (PCR: the polymerase chain reaction), (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (Antibodies) (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Coid Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993). II. Definitions The term "PD-1 axis-binding antagonist" is a molecule that inhibits the interaction of a PD-1 axis-binding partner with either one or more of its binding partners, in order to remove cell dysfunction. T resulting from signaling on the PD-1 signaling axis - the result being restoration or enhancement of T cell function (e.g., proliferation, cytokine production, destruction of the target cell). As used herein, a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist, and a PD-L2 binding antagonist. The term "PD-1 binding antagonist" is a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD -L1,PD-L2. In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate, or interfere with PD-1 binding. signal transduction resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one embodiment, a PD-1 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed in T-cell mediated signaling through PD-1 in order to make the cell Less dysfunctional dysfunctional T (e.g., enhancing effector responses to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In a specific aspect, a PD-1 binding antagonist is the MDX-1106 described herein. In a specific aspect, a PD-1 binding antagonist is the Merck 3745 described herein. In a specific aspect, a PD-1 binding antagonist is CT-011 described herein. In a specific aspect, a PD-1 binding antagonist is AMP-224 described herein. franconn / Lznz / E / YL - 44 The term “PD-L1 binding antagonist” is a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners. , such as PD-1, B7-1. In some embodiments, the PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits the binding of PDL1 to PD-L1. 1 and / or B7-1. In some embodiments, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate, or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1, B7-1. In one embodiment, a PD-L1 binding antagonist reduces negative costimulatory signaling mediated by or through expressed cell surface proteins in T cell-mediated signaling through PD-L1 in order to render a T cell dysfunctional less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, a PD-L1 binding antagonist is an anti-PD-L1 antibody. In a specific aspect, an anti-PD-L1 antibody is YW243.55.S70 described herein. In another specific aspect, an anti-Pd-L1 antibody is the MDX-1105 described herein. In yet another specific aspect, an anti-PD-L1 antibody is the MPDL3280A described herein. In another specific aspect, an anti-PD.L1 antibody is MEDI-4736 described herein. The term "PD-L2 binding antagonist" is a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1. In some embodiments, the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. In some embodiments, PD-L2 binding antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate, or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1. In one embodiment, a PD-L2 binding antagonist reduces negative costimulatory signaling mediated by or through expressed cell surface proteins in T cell-mediated signaling through PD-L2 in order to render a T cell dysfunctional less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, a PD-L2 binding antagonist is an immunoadhesin. The term "aptamer" refers to a nucleic acid molecule capable of binding to a target molecule, such as a polypeptide. For example, an aptamer of the invention can specifically bind to a TIGIT polypeptide, or to a molecule in a signaling pathway that modulates TIGIT expression. The generation and therapeutic use of aptamers are well established in the art. See, e.g., U.S. Pat. No. 5,475,096 and the therapeutic efficacy of Macugen® (Eyetech, New York) to treat age-related macular degeneration. The term "antagonist" is used in the broadest sense and includes any molecule that partially or totally blocks, inhibits, or neutralizes a biological activity of the native polypeptide described herein. So hanonn / i zoz / e / yl Similarly, the term "agonist" is used in the broadest sense and includes any molecule that mimics the biological activity of the native polypeptide described herein. Suitable agonist or antagonist molecules specifically include agonist or antagonist antibodies or antibody fragments, amino acid sequence fragments or variants of native polypeptides, peptides, antisense oligonucleotides, small organic molecules, etc. Methods for identifying agonists or antagonists of a polypeptide may comprise contacting a polypeptide with a candidate agonist or antagonist molecule and measuring a detectable change in one or more of the biological activities normally associated with the polypeptide. The terms "TIGIT antagonist" and "antagonist of TIGIT activity or TIGIT expression" are used interchangeably and refer to a compound that interferes with the normal functioning of TIGIT, either by decreasing transcription or translation of the nucleic acid encoding TIGIT, or by inhibiting or blocking the activity of the TIGIT polypeptide, or both. Examples of TIGIT antagonists include, but are not limited to, antisense polynucleotides, interfering RNAs, catalytic RNAs, RNA-DNA chimeras, TIGIT-specific aptamers, anti-TIGIT antibodies, TIGIT-binding fragments of anti-TIGIT antibodies , TIGIT-binding small molecules, TIGIT-binding peptides, and other polypeptides that specifically bind to TIGIT (including, but not limited to, TIGIT-binding fragments of one or more TIGIT ligands, optionally fused to one or more additional domains), such that the interaction between the TIGIT antagonist and TIGIT results in the reduction or cessation of TIGIT activity or expression. It will be understood by one of ordinary skill in the art that, in some cases, a TIGIT antagonist can antagonize one TIGIT activity without affecting another TIGIT activity. For example, a desirable TIGIT antagonist for use in certain methods herein is a TIGIT antagonist that antagonizes TIGIT activity in response to one of, PVR interaction, PCRL3 interaction, or PVRL2 interaction, e.g., without affect or minimally affect any of the other TIGIT interactions. The terms "PVR antagonist" and "antagonist of PVR activity or PVR expression" are used interchangeably and refer to a compound that interferes with the normal functioning of PVR, either by decreasing the transcription or translation of the PVR. nucleic acid encoding PVR, or by inhibiting or blocking the activity of the PVR polypeptide, or both. Examples of PVR antagonists include, but are not limited to, antisense polynucleotides, interfering RNAs, catalytic RNAs, RNA-DNA chimeras, PVR-specific aptamers, anti-PVR antibodies, PVR-binding fragments of anti-PVR antibodies , PVR-binding small molecules, PVR-binding peptides, and other polypeptides that specifically bind to PVR (including, but not limited to, PVR-binding fragments of one or more PVR ligands, optionally fused to one or more additional domains), such that the interaction between the PVR antagonist and PVR results in the reduction or cessation of PVR activity or expression. It will be understood by one of ordinary skill in the art that, in some cases, a PVR antagonist can antagonize one PVR activity without affecting another PVR activity. For example, a desirable PVR antagonist for use in certain methods herein is a PVR antagonist that antagonizes PVR activity in response to TIGIT interaction without affecting PVRhanonn / 1 znz / E / YL interactions. - 46 CD96 and / or PVR-CD226. The term "dysfunction" in the context of immune dysfunction refers to a state of reduced immune sensitivity to antigenic stimulation. The term includes the common elements of both exhaustion and anergy in which antigen recognition may occur, but the resulting immune response is ineffective in controlling infection or tumor growth. The term "dysfunctional" as used herein also includes refractory or insensitive to antigen recognition, specifically, an impaired ability to translate antigen recognition into downstream T cell effector functions, such as proliferation, production of cytokine (e.g., IL-2) and / or destruction of the target cell. The term "anergy" refers to the state of insensitivity to antigen stimulation that results from incomplete or insufficient signals delivered through the T cell receptor (e.g., increase in intracellular Ca+2 in the absence of ras activation). T cell anergy can also result to antigen stimulation in the absence of costimulation, resulting in the cell becoming refractory to subsequent activation by antigen even in the context of costimulation. The unresponsive state can often be overridden by the presence of interleukin-2. Anergic T cells do not undergo clonal expansion and / or acquire effector functions. The term "depletion" refers to T cell depletion as a state of T cell dysfunction arising from sustained TCR signaling that occurs during many chronic infections and cancer. It is distinguished from anergy in that it occurs not through incomplete or deficient signaling, but through sustained signaling. This is defined by low effector function, sustained expression of inhibitory receptors, and a transcriptional state distinct from that of functional effector or memory T cells. Depletion prevents optimal control of infection and tumors. Depletion can result from both extrinsic negative regulatory pathways (e.g., immunoregulatory cytokines) and cell intrinsic negative (co-stimulatory) regulatory pathways (PD-1, B7-H3, B7-H4, etc.). "Enhancing T cell function" means inducing, causing, or stimulating the T cell to have sustained or amplified biological function, or renewing or reactivating depleted or inactive T cells. Examples of enhancement of T cell function include; increased secretion of interferon-y from CD8+ T cells, increased proliferation, increased antigen sensitivity (e.g., viral, pathogen, or tumor clearance) relative to such levels before intervention. In one embodiment, the improvement level is at least 50%, alternatively, 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. The manner of measuring this improvement is known to those of ordinary skill in the art. A "dysfunctional T cell disorder" is a disorder or condition of T cells characterized by decreased sensitivity to antigenic stimulation. In a particular embodiment, a dysfunctional T cell disorder is a disorder that is specifically associated with increased inappropriate signaling through PD-1. In another embodiment, a dysfunctional T cell disorder is one in which the T cells are hQDQnn / I 7O7 / E / Yl - 47 energetic or have a decreased ability to secrete cytokines, to proliferate, or to perform cytolytic activity. In a specific aspect, decreased sensitivity results in ineffective control of a pathogen or of a tumor expressing an immunogen. Examples of dysfunctional T cell disorders characterized by T cell dysfunction include unresolved acute infection, chronic infection, and tumor immunity. "Tumor immunity" refers to a process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is "treated" when such evasion is attenuated, and tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinking, and tumor clearance. "Immunogenicity" refers to the ability of a particular substance to elicit an immune response. Tumors are immunogenic and enhancement of tumor immunogenicity helps clear tumor cells through the immune response. Examples of enhancement of tumor immunogenicity include, but are not limited to, treatment with a PD-1 axis-binding antagonist (e.g., anti-PD-L1 antibodies) and a TIGIT inhibitor (e.g., anti-TIGIT antibodies). "Sustained response" refers to the sustained effect in reducing tumor growth after cessation of treatment. For example, the size of the tumor may remain the same or smaller compared to its size at the start of the administration phase. In some modalities, the sustained response has a duration at least equal to the duration of treatment, at least 1.5 X, 2.0 X, 2.5 X, or 3.0 X the extent of the duration of treatment. The term "antibody" includes monoclonal antibodies (including full-length antibodies that have an immunoglobulin F region), antibody compositions with polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies, diabodies, and single-chain molecules), as well as antibody fragments. (e.g., Fab, F(ab')2 and Fv). The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein. The basic unit of 4-chain antibody is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. An IgM antibody consists of 5 of the basic heterotetramer units together with an additional polypeptide called a J chain, and contains 10 antigen-binding sites, while IgA antibodies comprise 2 to 5 of the 4-chain basic units that can polymerize. to form polyvalent assemblies in combination with the J chain. In the case of IgGs, the unit of 4 chains is generally about 150,000 daltons. Each L chain is linked to one H chain by a covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the isotype of the H chain. Each H and L chain it also has regularly spaced intrachain disulfide bridges. Each H chain has, at the N terminus, a variable (Vh) domain followed by three constant (Ch) domains for each of the o and y chains and four Ch domains for the μ and ε isotypes. Each L chain has, at the N-terminus, a variable (V1) domain followed by a constant domain at its other end. The Vl is aligned with the Vh and the Cl is aligned with the first constant domain of the franonn / Lznz / E / YL heavy chain. - 48 (CH1). The particular amino acid residues are considered to form an interconnection between the light chain and heavy chain variable domains. The pairing of Vh and Vl together forms a single antigen binding site. For the structure and properties of the different classes of antibodies, see e.g., Basic and Clinical Immunology, 8th Edition, Daniel P. Sties, Abba I. Terr, and Tristram G. Parsolw (eds), Appleton & Lange, Norwalk, CT, 1994, page 71 and chapter 6. The L chain of any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of its constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins IgA, IgD, IgE, IgG, and IgM, which have heavy chains designated o, δ, ε, y, and μ, respectively. The classes and and or are further divided into subclasses based on relatively minor differences in CH sequence and function, e.g., humans express the following subclasses: lgG1, lgG2A, lgG2B, lgG3, lgG4, lgA1, and lgA2. The "variable region" or "variable domain" of an antibody refers to the amino-terminal domains of the heavy or light chain of the antibody. The heavy chain and light chain variable domains may be referred to as "VH" and "VL", respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies in the same class) and contain the antigen binding sites. The term "variable" refers to the fact that certain segments of the variable domains differ widely in sequence between antibodies. The V domain mediates antigen binding and defines the specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the full extent of the variable domains. Rather, it is concentrated in three segments called hypervariable regions (HVRs) in both the light chain and heavy chain variable domains. The more highly conserved portions of the variable domains are called the framework regions (FR). The variable domains of the parental heavy and light chains each comprise four FR regions, mostly adopting a beta-sheet configuration, connected by three HVRs, which form loops that connect to, and in some cases form part of, the beta-sheet structure. . The HVRs on each chain are held together in close proximity by FR regions and, with the HVRs on the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Immunological Interest (Immunological Interest Sequences), Fifth Edition, National Institute of Health, Bethesda, MD (1991). The constant domains are not directly involved in the binding of the antibody to an antigen, but instead exhibit various effector functions, such as the involvement of the antibody in antibody-dependent cellular toxicity. The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and / or post-translational modifications (e.g., isomerizations, amidations) which may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations which typically include different antibodies directed against different hanonn / i zoz / e / yl determinants - 49 (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous since they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins. The "monoclonal" modifier indicates the character of the antibody that is obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present invention can be produced by a variety of techniques including, for example, the hybridoma method (e.g., Kohler and Milstein., Nature, 256:495- 97 (1975), Hongo et al., Hybridoma, 14 (3): 253-260 (1995), Harlow et al., Antibodies: A Laboratory Manual, (Coid Spring Harbor Laboratory Press, 2nd ed 1988), Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981), recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567), phage display technologies (see, e.g., Clackson et al., Nature, 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073- 1093 (2004), Fellouse, Proc. Nati. Acad. Sel. USA 101(34): 12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2): 119-132 (2004), and technologies for producing human or human-like antibodies in animals that have parts or all of the human immunoglobulin sites or genes encoding human immunoglobulin sequences (see, e.g., WO 1998 / 24893; WO 1996 / 34096; WO 1996 / 33735; WO 1991 / 10741; Jakobovits et al., Proc. Nati. Acad. Sel. USA 90: 2551 (1993); Jakobovits et al., Nature ( Nature) 362: 255-258 (1993); Bruggemann et al., Year in Immunol. 7:33 (1993); US Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,01 6; Marks et al., Bio / Technology 10: 779-783 (1992); Lonberg et al., Nature 368: 856-859 (1994); Morrison, Nature 368: 812-813 (1994); Fishwild et al ., Nature Biotechnol. 14: 845-851 (1996), Neuberger, Nature Biotechnol. 14: 826 (1996), and Lonberg and Huszar, Intern. Rev. Immunol. 13: 65-93 (1995). The term "empty antibody" refers to an antibody that is not conjugated to a cytotoxic or radiolabeled residue. The terms "full length antibody", "intact antibody" or "whole antibody" are used interchangeably to refer to an antibody in its substantially intact form, as opposed to an antibody fragment. Specifically complete antibodies include those with heavy and light chains that include an FC region. The constant domains can be native sequence constant domains (e.g., human native sequence constant domains) or their amino acid sequence variants. In some cases, the intact antibody may have one or more effector functions. An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen-binding and / or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2 and Fv fragments; diabodies; linear antibodies (see US Patent 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062

[1995] ); single chain antibody molecules and multispecific antibodies derived from antibody fragments. Papain digestion of the antibodies produced two identical hanonn / ι znz / E / Yl fragments. - 50 antigen-binding fragments called "Fab" and a residual "Fe" fragment, a designation reflecting the ability to crystallize easily. The Fab fragment consists of a complete L chain together with the variable region domain of the H chain (Vh), and the first constant domain of a heavy chain (Ch1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen binding site. Pepsin treatment of an antibody produces a single large F(abj2 fragment roughly corresponding to two disulfide-linked Fab fragments that has different antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab by having additional residues at the carboxy terminus of the Ch1 domain including one or more cysteines from the hinge region of the antibody Fab'-SH is the designation herein for a Fab' in which the residue(s) ) of cysteine ​​constant domains carry(n) a free thiol group.F(abj2) antibody fragments were originally produced as pairs of Fab' fragments that have linkage cysteines between them.Other chemical couplings of antibody fragments are also known. The Fe fragment comprises the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of antibodies are determined by the sequences in the Fe region, the region that is also recognized by the Fe receptors (FcR) found on certain cell types. "Fv" is the minimal antibody fragment that contains a complete antigen recognition and binding site. This fragment consists of a dimer of one heavy and one light chain variable region domain in tight non-covalent association. From the folding of these two domains emanate six hypervariable circuits (3 circuits each from the 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 comprising only three antigen-specific HVRs) has the ability to recognize and bind antigen, albeit at a lower affinity than the entire binding site. "Single chain Fv" also abbreviated as "sFv" or "scFv" are antibody fragments comprising the antibody Vh and Vl domains linked into a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the Vh and Vl domains that allows the sFv to form the desired structure for antigen binding. For a review of sFV, see Pluckthun in The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore eds., Springer Verlag, New York, pp. 269-315 (1994). "Functional fragments" of the antibodies of the invention comprise a portion of an intact antibody, generally including the antigen-binding or variable region of the intact antibody or the Fc region of an antibody that retains or has a binding ability to FcR. modified. Examples of the antibody fragments include linear antibody, single chain antibody molecules, and multispecific antibodies made up of antibody fragments. The term "diabodies" refers to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with short linkers (about 5 to 10 residues) between the Vh and Vl domains in such a way that inter-chain matching is achieved. but not intra-chain of V domains, hanonn / 1 znz / E / YL - 51 thus resulting in a bivalent fragment, i.e., a fragment having two antigen binding sites. Bispecific diabodies are heterodimers of two "crossover" sFv fragments in which the Vh and Vl domains of the two diabodies are present on different polypeptide chains. Diabodies are described in more detail, for example, in EP 404,097; WO 93 / 11161; Hollinger et al., Proc. nati. Acad. Sel. USA90: 6444-6448 (1993). Monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to the corresponding sequences in antibodies derived from a particular species or belonging to a class or subclass. particular antibody, as long as the rest of the chain(s) is identical or homologous to the corresponding sequences in antibodies derived from other species or belonging to another class or subclass of antibodies, as well as fragments of such antibodies, provided they exhibit the desired biological activity (U.S. Patent No. 4,816,567; Morrison et al., Proc. Nati. Acad. Sel. USA, 81:6851-6855 (1984)). Chimeric antibodies of interest herein include PRIMATIZED® antibodies wherein the antigen-binding region of the antibody is derived from an antibody produced, e.g., by immunizing macaque monkeys with the antigen of interest. As used herein, "humanized antibody" is used as a subset of "chimeric antibodies." "Humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one embodiment, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from a HVR (above defined) of the recipient are replaced by residues from a HVR from a non-human species (donor antibody) such as a mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and / or capacity. In some cases, framework residues ("FR") of the human immunoglobulin are replaced by corresponding non-human residues. In addition, humanized antibodies may comprise residues not found in the recipient antibody or the donor antibody. These modifications can be made to further refine antibody performance, such as binding affinity. In general, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the FR regions. are those of a human immunoglobulin sequence, although the FR regions may include one or more individual substitutions of the FR residue that improve antibody performance, such as isomerization binding affinity, immunogenicity, etc. The number of these amino acid substitutions in the FR is typically no more than 6 in the H chain and no more than 3 in the L chain. The humanized antibody will optionally also comprise at least a portion of a constant region (Fe ) of immunoglobulin, typically that of a human immunoglobulin. For additional details, see, e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also, for example, Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Pat. Nos. 6,982,321 and 7,087,409. hQHQnn / Lznz / E / Yli - 52 A "human antibody" is an antibody possessing an amino acid sequence corresponding to that of an antibody produced by a human and / or produced using any of the techniques for producing human antibodies as described herein. This definition of a human antibody specifically excludes a humanized antibody that comprises non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also available for the preparation of human monoclonal antibodies are the methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opinion. Pharmacol., 5: 368-74 (2001). Human antibodies can be prepared by administering the antigen to a transgenic animal that has been engineered to produce such antibodies in response to antigenic challenge, but whose endogenous sites have been disabled, e.g., immunized xeno-mice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 referring to XENOMOUSE™ technology). See also, for example, Li et al., Proc. nati. Acad. Sci. USA, 103:3557-3562 (2006) relating to human antibodies generated by human B-cell hybridoma technology. The term "hypervariable region", "HVR" or "HV" when used herein, refers to regions of an antibody variable domain that are hypervariable in sequence and / or that form structurally defined circuits. Antibodies generally comprise six HVRs; three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). In native antibodies, H3 and L3 display the greatest diversity of the six HVRs, and H3 in particular is considered to play a unique role in conferring fine specificity to antibodies. See e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu, in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003). Indeed, naturally occurring camelid antibodies consisting only of a heavy chain are functional and stable in the absence of the light chain. See, e.g., HamersCasterman et al., Nature 363:446-448 (1993); Sheriff et al., Nature Struct. Biol. 3:733-736 (1996). A number of HVR delineations are in use and are covered herein. Kabat complementarity determining regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Chothia refers instead to the location of the structural circuits (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). AbM HVRs represent a compromise between Kabat HVRs and Chothia structural circuits and are used by Oxford Molecular's AbM antibody modeling software. “Contact” HVRs are based on an analysis of the available complex crystal structures. The residues of each of these HVRs are noted below. hQHQnn / Lznz / E / Yli Circuit Kabat AbM Chothia Contact L1 L24-L34 L24-L34 L26-L32 L30-L36 L2 L50-L56 L50-L56 L50-L52 L46-L55 L3 L89-L97 L89-L97 L91-L96 L89-L96 H1 H31-H35B H26-H35B H26-H32 H30-H35B (Kabat numbering) H1 H31-H35 H26-H35 H26-H32 H30-H35 (Chothia numbering) H2 H50- H65 H50-H58 H53-H55 H47-H58 H3 H95-H102 H95-H102 H96-H101 H93-H101 hQHQnn / Lznz / E / Yli HVRs can comprise “extended HVRs” as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) on the VL and 26-35 (H1), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH. Variable domain residues are numbered according to Kabat et al., supra, for each of these definitions. The term "variable domain residue numbering as in Kabat" or amino acid position numbering as in Kabat", and variations thereof, refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or an insertion into, a FR or HVR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after H2 residue 52 and inserted residues (e.g., residues 82a, 82b and 82c, etc., according to Kabat) after residue 82 of the heavy chain FR. The Kabat numbering of residues can be determined for a given antibody by aligning the regions of homology of the antibody sequence with a standard "Kabat numbered" sequence. "Framework" or "FR" residues are those variable domain residues other than HVR residues as defined herein. A "human consensus framework" or a human acceptor framework" is a framework representing the amino acid residues that most commonly occur in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences comes from a subset of variable domain sequences. Generally, the sequence subset is a subset as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include, for the VL, the subgroup can be the kappa I, kappa II, kappa III or kappa IV subgroup as in Kabat et al., supra. Additionally, for VH, the subgroup can be subgroup I, subgroup II, or subgroup II as in Kabat et al., supra. Alternatively, a human consensus framework can be derived from the above at their particular residues, such as when a human framework residue is selected based on its homology to the donor framework by aligning the donor framework sequence with a collection of diverse framework sequences. human. A human acceptor framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof or may contain pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. . A "VH subgroup III consensus structure" comprises the consensus sequence obtained from the amino acid sequences in variable heavy subgroup III of Kabat et al., supra. In one embodiment, the VH subgroup III consensus framework amino acid sequence comprises at least a portion of or all of the following sequences: EVQLVESGGGLVQPGGSLRLSCAAS (HC-FR1) (SEQ ID NO: 25), WVRQAPGKGLEWV (HC-FR2), (SEQ ID NO: 26), RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (HC-FR3, SEQ ID NO: 27), WGQGTLVTVSA (HC-FR4), ( SEQ ID NO: 28). A "VL kappa I consensus framework" comprises the consensus sequence obtained from the amino acid sequences in the variable light kappa I subgroup of Kabat et al., supra. In one embodiment, the VH subgroup I consensus framework amino acid sequence comprises at least a portion of or all of each of the following sequences: DIQMTQSPSSLSASVGDRVTITC (LC-FR1) (SEQ ID NO: 29), WYQQKPGKAPKLLIY (LC-FR2) (SEQ ID NO: 30), GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (LC-FR3) (SEQ ID NO: 31), FGQGTKVEIKR (LC-FR4) (SEQ ID NO: 32). An "amino acid modification" at a specified position, e.g., of the Fe region, refers to the substitution or deletion of the specified residue, or the insertion of at least one amino acid residue adjacent to the specified residue. Insertion "adjacent" to a specified residue means an insertion within one to two residues thereof. The insertion can be N-terminal or C-terminal to the specified residue. The presently preferred amino acid modification is a substitution. An "affinity matured" antibody is one with one or more alterations in one or more of its HVRs that results in an improvement in the affinity of the antibody for the antigen, compared to a parent antibody that does not possess that(s). alteration(s). In one embodiment, an affinity matured antibody has nanomolar or even picomolar affinities for the target antigen. Marks et al., Bio / Technology 10:779-783 (1992) describe affinity maturation by VH and VL domain mixing. Random mutagenesis of HVR and / or framework residues is described, for example, by: Barbas et al., Proc. Nat. Acad. ICS. USA 91:3809-3813 (1994); Schier et al. Gene 169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkinsethal, J. Mol. Biol. 226:889-896 (1992). As used herein, the term "binds specifically to" or "specific to" refers to measurable and reproducible interactions such as binding between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules. For example, an antibody that specifically binds to a target (which may be an epitope) is an antibody that binds to this target with greater affinity, avidity, more readily, and / or longer duration than it does to other targets. . In one embodiment, the degree of binding of an antibody to an unrelated target is less than about 10% day binding of the antibody to the target as measured, e.g., by means of a radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a Franonn / Lznz / E / YL constant. - 55 dissociation (Kd) of < 1 μΜ, 100 nM, 10 nM, ≥ 1 nM, or ≥ 0.1 nM. In certain embodiments, an antibody specifically binds to an epitope on a protein that is conserved among proteins from different species. In another embodiment, the specific join may include, but does not require, an exclusive join. As used herein, the term "immunoadhesin" designates antibody-like molecules that combine the binding specificity of a heterologous protein (an adhesin) with the effector functions of immunoglobulin constant domains. Structurally, immunoadhesins comprise a fusion of a amino acid sequence with desired binding specificity that is different from the antigen recognition and binding site of an antibody (i.e., is “heterologous”), and from an immunoglobulin constant domain sequence The adhesin part of an immunoadhesin molecule is typically a contiguous amino acid sequence comprising at least the binding site of a receptor or ligand The immunoglobulin constant domain sequence in the immunoadhesin can be derived from any immunoglobulin, such as IgG-1, IgG-2 (including IgG2A and IgG2B), IgG-3, or IgG-4, IgA (including IgA-1 and IgA-2), IgE, IgD, or IgM subtypes. Ig fusions preferably include substitution of a domain of a polypeptide or antibody described in the present in place of at least one variable region within an Ig molecule. In a particularly preferred embodiment, the immunoglobulin fusion includes the hinge, CH2 and CH3, or CH1, CH2 and CH3 regions of an lgG1 molecule. For the production of immunoglobulin fusions as second drugs useful for combination therapy herein include polypeptides comprising the extracellular or PD-1 binding portions of PD-L1 or PD-L2 or the extracellular or PD-L1 binding portions or PD-L2 of PD-1, fused to a constant domain of an immunoglobulin sequence, such as a PD-L1 ECD-Fc, a PD-L2 ECD-Fc, and a PD-1 ECD-Fc, respectively. Combinations of IgFe immunoadhesin and ECD of cell surface receptors are sometimes referred to as soluble receptors. A "fusion protein" and a "fusion polypeptide" refer to a polypeptide that has two moieties covalently linked together, where each of the moieties is a polypeptide having a different property. The property may be a biological property, such as in vitro or in vivo activity. The property can also be a simple chemical or physical property, such as binding to a target molecule, catalysis of a reaction, etc. The two portions may be linked directly via a single peptide bond or via a peptide linker, but be in reading frame of each other. A "PD-1 oligopeptide", "PD-L1 oligopeptide" or "PD-L2 oligopeptide" is an oligopeptide that binds, preferably specifically, to a PD-1, PD-L1 or PD-negative costimulatory polypeptide. L2, respectively, including a receptor, ligand or signaling component, respectively, as described herein. Such oligopeptides can be chemically synthesized using known oligopeptide synthesis methodology or can be prepared and purified using recombinant technology. Such oligopeptides are commonly at least about 5 amino acids in length, alternatively at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 amino acids in length or more. Such oligopeptides can be identified using well known techniques. In this regard, it is noted that techniques for screening oligopeptide libraries for oligopeptides with the ability to specifically bind to a target polypeptide are well known in the art (see, e.g., U.S. Patent Nos. 5,556,762, 5,750,373, 4,708,871, 4,833,092, 5,223,409 Geysen et al., Proc. Nati Acad Sci USA 82:178 182 (1985) Geysen et al., in Synthetic Peptides as Antigens 130-149 (1986) Geysen et al., J. Immunol. Meth., 102:259-274 (1987), Schoofs et al., J. Immunol., 140:611-616 (1988), Cwirla, S.E. et al. Proc. Nati. Acad. Sci. USA, 87:6378 (1990 ); Lowman, H.B. et al. Biochemistry, 30:10832 (1991); Clackson, T. et al. Nature, 352: 624 (1991); Marks, J. D. et al., J. Mol. Biol., 222:581 (1991), Kang, A.S. et al. Proc. Nati. Acad. Sci. USA, 88:8363 (1991), and Smith, G.P., Current Opin. Biotechnol., 2:668 (1991). A "blocking antibody" or an antagonistic antibody" is one that inhibits or reduces a biological activity of the antigen to which it binds. In some embodiments, blocking antibodies or antagonistic antibodies substantially or completely inhibit the biological activity of the antigen. The anti-PD-L1 antibodies of the invention block signaling through PD-1 in order to restore the functional response by T cells (e.g., proliferation, cytokine production, target cell killing) of a dysfunctional state to antigen stimulation. An "agonist" or "activating" antibody is one that enhances or initiates signaling by the antigen to which it binds. In some embodiments, agonist antibodies cause or activate signaling without the presence of the natural ligand. The term Fe region" is used herein to define a C-terminal region of an immunoglobulin heavy chain, including native sequence Fe regions and variant Fe regions. Although the boundaries of the Fe region of an immunoglobulin heavy chain may vary, the Fe region of human IgG heavy chain is commonly defined as stretching from an amino acid residue at position Cys226 or from Pro230, to the carboxyl terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fe region can be removed, for example, during production or purification of the antibody, or by recombinantly making the nucleic acid encoding the heavy chain. of the antibody. Accordingly, an intact antibody composition can comprise antibody populations with all K447 residues removed, antibody populations with no K447 residue removed, and antibody populations having a mixture of antibodies with and without the K447 residue. Native sequence F regions for use in the antibodies of the invention include human IgG1, IgG2 (IgG2A, IgG2B), IgG3 and IgG4. Fe" or FcR" receptor describes a receptor that binds to the Fe region of an antibody. The preferred FcR is a native sequence human FcR. In addition, a preferred FcR is one that binds to an IgG antibody (a receptor gamma) and includes receptors of the FcyRI, FcyRIl, and FcyRIII subclasses, including allelic variants and hQHQnn / I 7O7 / E / Yl. - 57 alternatively spliced ​​forms of these receptors, FcyRII receptors including FcyRIIA (an "activation receptor") and FcyRIIB (an "inhibition receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. The FcyRIIA activation receptor contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The inhibition receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain. (See, M. Daéron, Annu. Rev. Immunol. 15:203-234 (1997). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991); Capel et al. , Immunomethods 4: 25-34 (1994) and de Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995).Other FcRs, including those to be identified in the future, are covered by the term “FcR” herein. The term "Fe" receptor or "FcR" also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus. Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994). Methods for measuring FcRn binding are known (see, e.g., Ghetie and Ward, Immunol. Today 18: (12): 592-8 (1997); Ghetie et al., Nature Biotechnology 15 (7): 637-40 (1997), Hinton et al., J. Biol. Chem. 279(8): 6213-6 (2004), WO 2004 / 92219 (Hinton et al.) FcRn binding in vivo and life Serum media of high-affinity binding polypeptides to human FcRn can be assayed, e.g., in transgenic mice or in transfected human cell lines expressing human FcRn, or in primates that can be administered polypeptides having a variant Fc region. 2004 / 42072 (Presta) describes antibody variants that enhance or decrease binding to FcRs See also e.g., Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001). The phrase "substantially reduced" or "substantially different" as used herein, denotes a sufficiently high degree of difference between two numerical values ​​(generally one associated with a molecule and the other associated with a reference / comparator molecule) such that that the person skilled in the art will consider the difference between the two values ​​of statistical significance within the context of the biological characteristic measured by means of said values ​​(e.g., the Kd values). The difference between said two values ​​is, for example, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, and / or greater than about 50% as a function of the value for the reference / comparator molecule. The term "substantially similar" or "substantially the same" as used herein denotes a sufficiently high degree of similarity between two numerical values ​​(for example, one associated with an antibody of the invention and the other associated with an antibody of reference / comparator), such that the person skilled in the art will consider the difference between the two values ​​of little or no biological and / or statistical significance within the context of the biological characteristic measured by said values ​​(e.g., the Kd values). The difference between said two values ​​is, for example, less than about 50%, less than about 40%, less than about 30%, less than about 20%, and / or less than about 10% as a function of the reference value. / comparator. "Carriers" as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are non-toxic to the cell or mammal exposed thereto at the doses and hQHQnn / Lznz / E / Yli - 58 concentrations used. Frequently, the physiologically acceptable vehicle is a pH buffered aqueous solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight polypeptides (less than about 10 residues); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or Usine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™. A package insert” refers to instructions commonly included in commercial drug packages that contain information about the indications commonly included in commercial drug packages that contain information about the indications, usage, dosage, administration, contraindications, other medications that are combined with the packaged product, and / or warnings about the use of such medications, etc. As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of the individual or cell being treated during the course of a clinical pathology. Desirable effects of treatment include slowing the rate of disease progression, improving or alleviating the disease state, and remitting or improving the prognosis. For example, an individual is successfully "treated" if one or more of the symptoms associated with cancer are mitigated or eliminated, including, but not limited to, the growth of (or are killed) cancer cells, the symptoms decrease resulting from the disease, the quality of life of those suffering from the disease is increased, the dose of other drugs required to treat the disease is decreased, the progression of the disease is delayed and / or the survival of individuals is prolonged. As used herein, "slowing the progression of a disease" means to defer, hinder, delay, delay, stabilize, and / or postpone the development of a disease (such as cancer). This delay can be of variable lengths of time, depending on the history of the disease and / or the individual treated. As is apparent to the person skilled in the art, a sufficient or significant delay may indeed encompass prevention in which the individual does not develop the disease. For example, end-stage cancer, such as the development of metastases, can be delayed. As used herein, "cancer relapse reduction or inhibition" means to reduce or inhibit tumor or cancer relapse or tumor or cancer progression. As used herein, "cancer" and "cancerous" refer to or describe the physiological condition in mammals typically characterized by unregulated cell growth. Included in this definition are benign and malignant cancers as well as latent tumors or micrometastases. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include squamous cell cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung), cancer of the peritoneum, cancer hQHQnn / L7R7 / B / YI - 59 hepatocellular, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial carcinoma or uterine cancer, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, and various types of head and neck cancer, as well as B-cell lymphoma (including Low-grade / follicular non-Hodgkin lymphoma (NHL); small lymphocytic NHL (SL); intermediate-grade / follicular NHL; diffuse intermediate-grade NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; small cell NHL high-grade undivided; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatosis, edema (such as that associated with brain tumors), and Meigs syndrome. As used herein, "metastasis" means the spread of cancer from its primary site to other places in the body. Cancer cells can break away from a primary tumor, enter the lymphatics and blood vessels, circulate through the bloodstream, and grow in a distant location (metastasize) to normal tissues anywhere in the body. The metastasis can be local or distant. Metastasis is a sequential process, dependent on tumor cells breaking away from the primary tumor, traveling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within the tumor cell regulate its behavior, and interactions between the tumor cell and host cells at the distant site are also significant. An "effective amount" is at least the minimum concentration required to effect amelioration or medial prevention of a particular disorder. An amount effective herein may vary according to factors such as the disease state, age, gender, and weight of the patient, and the ability of the antibody to elicit the desired response in the individual. An effective amount is also one in which any harmful or toxic effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired outcomes include outcomes such as elimination or reduction of risk, decrease in severity or delay of disease onset including biochemical, histological and / or behavioral symptoms of the disease, its complications and the intermediate pathological phenotypes that occur during the development of the disease. For therapeutic use, beneficial or desired results include clinical results such as a decrease in one or more symptoms resulting from the disease, an increase in the quality of life of those suffering from the disease, a decrease in the dose of other medications required to treat the disease, enhancement of the effect of other drugs such as through targeting, delay of disease progression and / or prolongation of survival. In the case of cancer or a tumor, an effective amount of the drug may have the effect of reducing the number of cancer cells; reducing the size of the tumor; inhibiting (i.e., delaying to some extent or desirably stopping) hQHQnn / Lznz / E / Yli cell infiltration - 60 cancerous in peripheral organs; inhibition (i.e., delay to some extent or desirably stop) tumor metastasis; inhibition to some extent of tumor growth; and / or alleviation to some extent of one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of the drug, compound, or pharmaceutical composition is an amount sufficient to effect prophylactic or therapeutic treatment either directly or indirectly. As understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, "an effective amount" may be considered in the context of administering one or more therapeutic agents and providing a single agent in an effective amount may be considered if, in conjunction with one or more other agents, a desirable result can or is achieved. As used herein, "in conjunction with" refers to the administration of one treatment modality in addition to another treatment modality. As such, "in conjunction with" refers to the administration of one treatment modality before, during, or after the administration of the other treatment modality to the individual. As used herein, "subject" means a mammal including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline. Preferably, the subject is a human. Herein patients are also subjects. As used herein, "complete response" or "CR" refers to the disappearance of all target lesions; “partial response” or “PR” refers to at least a 30% decrease in the sum of the longest diameters (SLD) of the target lesions, from baseline SLD; and “stable disease” or “SD” refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, based on the smallest SLD since treatment initiation. As used herein, "progressive disease" or "PD" refers to at least a 20% increase in the SLD of the target lesions, taking as reference the smallest SLD recorded since the start of treatment or the presence of one or more new lesions. As used herein, "progression-free survival" (PFS) refers to the extension of time during and after treatment during which the disease being treated (e.g., cancer) does not worsen. Progression-free survival can include the amount of time that patients have experienced a complete response or partial response, as well as the amount of time that patients have experienced stable disease. As used herein, "total response rate" (ORR) refers to the sum of the complete response rate (CR) and the partial response rate (PR). As used herein, "overall survival" refers to the percentage of individuals in a group with a probability of life after a particular length of time. A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Examples of hQHQnn / Lznz / E / Yli - 61 therapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bulatacin and bulatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapacone; lapacol; colchicines; betulinic acid; a camptothecin (including the synthetic analogue topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; pemetrexed; calistatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin and bizelesin); podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; TLK-286; CDP323, an inhibitor of oral alpha-4 integrin; a sarcodictiin; spongistatin; nitrogen gases such as chlorambucil, chlornaphazine, colophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicin, phenesterine, prednimustine, trofosphamide, uracil gas; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediin antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33: 183-186 (1994)); dynemycin, including dynemycin A; a esperamycin; as well as neocarzinostatin chromophore and related enediin chromoprotein antibiotic chromophores), aclacinomycins, actinomycin, autramycin, azaserin, bleomycins, cactinomycin, carabicin, carminomycin, carzinophyllin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, doxorubicin (including ADRIAMICIN®, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin HCI liposome injection (DOXIL®), and deoxidoxorubicin), epirubicin, esorubicin, idarubicin , marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, chelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), an epothilone, and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, and imatinib (a 2-phenylaminopyrimidine derivative), as well as other inhibitors of team c; antiadrenals such as aminoglutethimide, mitotane, trilostane; folic acid filler such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisanthrene; edatrexate; defofamine; demecolcine; Diaziquone; elfornitin; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerin; pentostatin; fenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triazicuone; 2,2',2-tnclorotriet¡lamina; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidin); urethane; vindesine (ELDISINE®, FILDESIN®); dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; hanonn / i zoz / e / yl - 62 gacytosine; arabinoside (Ara-C); thiotepa; taxoids, e.g., paclitaxel (TAXOL®), nanoparticle formulation made from paclitaxel albumin (ABRAXANETM), and doxetaxel (TAXOTERE®); chloranbucil; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine (VELBAN®); platinum; etoposide (VP16); ifosfamide; mitoxantrone; Vincristine (ONCOVIN®); oxaliplatin; leucovovin; vinorelbine (NAVELBINE®); novantron; edatrexate; daunomycin; aminopterin; ibandronate; RFS 2000 topoisomerase inhibitor; difluoromethylornithine (DMFO); retinoids such as retinoic acid; pharmaceutically acceptable salts, acids or derivatives of any of the foregoing; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, an abbreviation for a treatment regimen of oxaliplatin (ELOXATINTM) combined with 5-FU and leucovovin. Also included in this definition are anti-hormonal agents that act to regulate, reduce, block, or inhibit the effects of hormones that can promote cancer growth and are often in the form of systemic, or whole-body treatment. These may be hormones themselves. Examples include anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX® tamoxifen), raloxifene (EVISTA®), droloxifene, 4-hydroxytamoxifen, trioxifen, ketoxifen, LY117018, onapristone, and toremifene (FARESTON®); anti-progesterones; estrogen receptor downregulators (ERDs); estrogen receptor antagonists such as fulvestrant (FASLODEX®); agents that function to suppress or inactivate the ovaries, for example, leutinizing hormone-releasing hormone (LHRH) agonists such as leuprolide acetate (LUPRON® and ELIGARD®), goserelin acetate, buserelin acetate, and tripterelin; anti-androgens such as flutamide, nilutamide and bicalutamide; and aromatase inhibitors that inhibit the aromatase enzyme, which regulates the production of estrogen in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate (MEGASE®), exemestane (AROMASIN®) , formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®). Additionally, such definition of chemotherapeutic agents includes bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate ( AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); as well as troxacitabine (a cytosine nucleoside analogue of 1,3-dioxolane); antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in aberrant cell proliferation, such as, for example, PKC-alpha, Raf, Η-Ras, and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine and gene therapy vaccines, eg, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; topoisomerase 1 inhibitor (e.g., LURTOTECAN®); an anti-estrogen such as fulvestrant; a Kit inhibitor such as imatinib or EXEL-0862 (a tyrosine kinase inhibitor); an EGFR inhibitor such as erlotinib or cetuximab; an anti-VEGF inhibitor such as bevacizumab; irinotecan; rmRH (e.g., ABARELIX®); lapatinib and lapatinib ditosylate (a dual small molecule ErbB-2 and EGFR tyrosine kinase inhibitor also known as GW572016); 17AAG (a derivative of geldanamycin which is a 90 poison heat shock protein (Hsp), and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. franconn / Lznz / E / YL - 63 As used herein, the term "cytokine" refers generically to proteins released by one cell population that act in another cell as intercellular mediators or have an autocrine effect in the cells that produce the proteins. Examples of such cytokines include lymphokines, monokines; interleukins ("ILs") such as IL-1, IL-1a, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL10, IL-11, IL-12, IL-13, IL-15, IL-17A-F, IL-18 to IL-29 (such as IL-23), IL-31, including PROLEUKIN® rlL-2; a tumor necrosis factor such as TNF-α or TNF-β, TGFβ1-3; and other polypeptide factors including leukemia inhibitory factor (LlF"), ciliary neurotrophic factor ("CNTF"), CNTF-like cytokine ("CLC"), cardiotropin ("CT"), and kit ligand ("KL"). As used herein, the term "chemokine" refers to soluble factors (e.g., cytokines) that have the ability to selectively induce leukocyte chemotaxis and activation. They also trigger processes of angiogenesis, inflammation, wound healing, and tumorigenesis. Examples of chemokines include IL-8, a human homologue of keratinocyte chemoattractant (KC). As used herein and in the appended claims, the singular formulas a", "or", and "the" include referents to the plural unless the context clearly dictates otherwise. Reference to "about" a value or parameter herein includes (and describes) variations directed at that value or parameter per se. For example, the description referring to about X" includes the description of X". The phrase "pharmaceutically acceptable salt" as used herein refers to pharmaceutically acceptable inorganic or organic salts of a compound of the invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate. , pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate salts (i.e., 1,Γ- methylene bis-(2-hydroxy¡-3naphthoate)), alkali metal salts (e.g., sodium and potassium), alkaline earth metal salts (e.g., magnesium), and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or a counter ion. The counter ion can be any organic or inorganic residue that stabilizes the charge in the parent compound. Furthermore, -a pharmaceutically acceptable salt may have more than one charged atom in its structure. Examples where multiple charged atoms are part of the pharmaceutically acceptable salt may have multiple counter ions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counter ions. If the compound of the invention is a base, the desired pharmaceutically acceptable salt can be prepared by any method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidylic acid, such as glucuronic acid, or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, a hQDQnn / I 7O7 / E / Yl· - 64 amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), a alkali metal hydroxide or an alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines, such as potassium, magnesium, manganese, iron, copper, zinc , aluminum and lithium. The phrase "pharmaceutically acceptable" indicates that the substance or composition must be chemically and / or lexicologically compatible with the other ingredients that comprise the formulation and / or with the mammal treated with it. The aspects and variations of the invention described herein are understood to include "consisting" and / or "consisting essentially of" the aspects and variations. III. methods In one aspect, there is provided herein a method of treating or slowing the progress of cancer in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. In another aspect, there is provided herein a method of reducing or inhibiting cancer recurrence or cancer progression in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with a agent that decreases or inhibits the expression and / or activity of TIGIT. As described herein, cancer recurrence and / or cancer progression includes, without limitation, cancer metastasis. In another aspect, there is provided herein a method of treating or slowing the progression of an immune-related disease in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with a agent that decreases or inhibits the expression and / or activity of TIGIT. In another aspect, there is provided herein a method of reducing or inhibiting the progression of an immune-related disease in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with a agent that decreases or inhibits the expression and / or activity of TIGIT. In some modalities, the immune related disease is associated with a dysfunctional T cell disorder. In some modalities, the immune related disease is a viral infection. In certain embodiments, the viral infection is a chronic viral infection. In some embodiments, the dysfunctional T-cell disorder is characterized by decreased sensitivity to antigenic stimulation. In some modalities, the dysfunctional T-cell disorder is characterized by T-cell anergy or hQHQnn / L7R7 / B / YI capacity. - 65 decreased to secrete cytokines, to proliferate, or to perform cytolytic activity. In some embodiments, the dysfunctional T cell disorder is characterized by depletion of T cells. In some embodiments, the T cells are CD4+ and CD8+ T cells. In some modalities, dysfunctional T cell disease includes unresolved acute infection, chronic infection, and tumor immunity. In another aspect, there is provided herein a method of increasing, improving or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. In another aspect, there is provided herein a method of treating or slowing the progression of cancer in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or or the activity of CD226. In another aspect, there is provided herein a method of reducing or inhibiting cancer recurrence or cancer progression in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or activity of CD226. In another aspect, there is provided herein a method of treating or slowing the progression of an immune-related disease in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or activity of CD226. In another aspect, there is provided herein a method of reducing or inhibiting the progression of an immune-related disease in an individual, comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or activity of CD226. In some modalities, the immune related disease is associated with a dysfunctional T cell disorder. In some modalities, the immune related disease is a viral infection. In certain embodiments, the viral infection is a chronic viral infection. In some embodiments, the dysfunctional T-cell disorder is characterized by decreased sensitivity to antigenic stimulation. In some embodiments, the dysfunctional T cell disorder is characterized by T cell anergy or decreased ability to secrete cytokines, to proliferate, or to perform cytolytic activity. In some embodiments, the dysfunctional T cell disorder is characterized by depletion of T cells. In some embodiments, the T cells are CD4+ and CD8+ T cells. In some embodiments, the immune-related disease is selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity. In another aspect, there is provided herein a method of increasing, improving or stimulating an immune response or function in an individual by administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the expression and / or or the activity of CD226. In some embodiments, the agent that modulates CD226 expression and / or activity has the ability to increase and / or stimulate CD226 expression and / or activity; to increase and / or stimulate the interaction of CD226 with PVR, PVRL2 and / or PVRL3; and to increase and / or stimulate intracellular signaling mediated hQHQnn / I 7O7 / E / Yl· - 6 6by binding of CD226 to PVR, PVRL2 and / or PVRL3. As used herein, an agent capable of increasing and / or stimulating the expression and / or activity of CD226 includes, without limitation, agents that increase and / or stimulating the expression and / or activity of CD226. As used herein, the agent capable of increasing and / or stimulating the interaction of CD226 with PVR, PVRL2 and / or PVRL3 includes, without limitation, agents that increase and / or stimulating the interaction of CD226 with PVR, PVRL2 and / or or PVRL3. As used herein, the agent capable of increasing and / or stimulating intracellular signaling mediated by the binding of CD226 to PVR, PVRL2, and / or PVRL3 includes, without limitation, agents that increase and / or stimulate intracellular signaling mediated by the binding of CD226 to PVR, PVRL2 and / or PVRL3. In some embodiments, the agent that modulates CD226 expression and / or activity is selected from an agent that inhibits and / or blocks the interaction of CD226 with TIGIT, an antagonist of TIGIT expression and / or activity, an antagonist of PVR expression and / or activity, an agent that inhibits and / or blocks the interaction of TIGIT with PVR, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL2, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL3, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVRL2, an agent that inhibits and / or blocks intracellular signaling mediated by TIGIT binding to PVRL3 and combinations thereof. In some embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. . In some embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is an anti-TIGIT antibody or an antigen-binding fragment thereof. In some embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is an inhibitory nucleic acid selected from an antisense polynucleotide, an interfering RNA, a catalytic RNA, and a RNA-DNA chimera. In some embodiments, the antagonist of TIGIT expression and / or activity is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody or an antigen-binding fragment thereof. In some embodiments, the antagonist of TIGIT expression and / or activity is an inhibitory nucleic acid selected from an antisense polynucleotide, RNA interference, catalytic RNA, and RNA-DNA chimera. In some embodiments, the antagonist of PVR expression and / or activity is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the antagonist of PVR expression and / or activity is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. . In some modalities, the agent that inhibits and / or blocks the interaction of TIGIT with PVR is a hanonn / i zoz / e / yl - 67 small molecule inhibitor, an inhibitory antibody or an antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks the interaction of TIGIT with PVR is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory nucleic acid. inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks the interaction of TIGIT with PVRL2 is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory nucleic acid. inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks the interaction of TIGIT with PVRL3 is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory nucleic acid. inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid , and an inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an acid inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks intracellular signaling mediated by TIGIT binding to PVRL2 is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an acid inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks intracellular signaling mediated by TIGIT binding to PVRL3 is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an acid inhibitory nucleic acid, and an inhibitory polypeptide. In another aspect, provided herein is a method of increasing, improving, or stimulating an immune response or function in an individual by administering to the individual an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent which decreases or inhibits the expression and / or activity of one or more additional co-inhibitory immune receptors. In some embodiments, the one or more additional immune co-inhibitory receptors are selected from PD-1, CTLA-4, LAG3, TIM3, BTLA VISTA, B7H4, and CD96. In some embodiments, the one or more additional immune co-inhibitory receptors are selected from PD-1, CTLA-4, LAG3 and TIM3. In another aspect, provided herein is a method of increasing, improving, or stimulating an immune response or function in an individual by administering to the individual an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent that increases or activates the expression and / or activity of one or more additional co-stimulatory immune receptors. In some embodiments, the one or more additional immune costimulatory receptors are selected from CD226, OX-40, CD28, CD27, CD137, HVEM, GITR, MICA, ICOS, NKG2D, and 2B4. In some modalities, the one or more immune co-stimulatory receptors hanonn / i zoz / e / yl - An additional 68 are selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and GITR. In some embodiments, the one or more additional immune costimulatory receptors are selected from OX-40 and CD27. The methods of this invention may find use in the treatment of conditions where improved immunogenicity is desired such as increasing tumor immunogenicity for the treatment of cancer or T-cell dysfunctional disorders. A variety of cancers can be treated, or their progression can be slowed. In some embodiments, the individual has non-small cell lung cancer. Non-small cell lung cancer can be found at an early stage or at the end stage. In some embodiments, the individual has small cell lung cancer. Small cell lung cancer can be found at an early stage or at the end stage. In some embodiments, the individual has renal cell cancer. Renal cell cancer can be found at an early stage or at the end stage. In some embodiments, the individual has colorectal cancer. Colorectal cancer can be found in the early stage or in the terminal stage. In some embodiments, the individual has ovarian cancer. Ovarian cancer can be found in an early stage or in the terminal stage. In some embodiments, the individual has breast cancer. Breast cancer can be found in an early stage or in the terminal stage. In some embodiments, the individual has pancreatic cancer. Pancreatic cancer can be found at an early stage or at the end stage. In some embodiments, the individual has gastric carcinoma. Gastric carcinoma can be found at an early stage or at the end stage. In some embodiments, the individual has bladder cancer. Bladder cancer can be found at an early stage or at the end stage. In some embodiments, the individual has esophageal cancer. Esophageal cancer can be found at an early stage or at the end stage. In some embodiments, the individual has mesothelioma. Mesothelioma can be found in an early stage or in the terminal stage. In some embodiments, the individual has melanoma. Melanoma can be found at an early stage or at the end stage. In some embodiments, the individual has head and neck cancer. Head and neck cancer can be found in an early stage or in the terminal stage. In some embodiments, the individual has thyroid cancer. Thyroid cancer can be found at an early stage or at the end stage. In some embodiments, the individual has a sarcoma. The sarcoma can be in the early stage or in the end stage. In some embodiments, the individual has prostate cancer. Prostate cancer can be found in an early stage or in the terminal stage. In some embodiments, the individual has glioblastoma. Glioblastoma can be found in an early stage or in the end stage. In some embodiments, the individual has cervical cancer. Cervical cancer can be found in an early stage or in the terminal stage. In some embodiments, the individual has thymic carcinoma. Thymic carcinoma can be found at an early stage or at the end stage. In some embodiments, the individual has leukemia. Leukemia can be found in an early stage or in the terminal stage. In some embodiments, the individual has lymphoma. Lymphoma can be found in an early stage or in the end stage. In some embodiments, the individual has myelomas. Myelomas can be found at an early stage or at the end stage. In some embodiments, the individual has mycosis fungoides. Mycosis fungoides can be found in an early stage or in the terminal stage. In some hanonn / ι znz / E / Yl· - 69 modalities, the individual has Merkel cell cancer. Merkel cell cancer can be found at an early stage or at the end stage. In some embodiments, the individual has hematologic diseases. Hematological diseases can be found in an early stage or in a terminal stage. In some embodiments, the individual is a human. In some embodiments of the methods of this invention, CD4 and / or CD8 T cells in the individual have increased or enhanced pre-stimulation, activation, proliferation, cytokine release and / or cytolytic activity, relative to prior to administration. of the combination. In some embodiments of the methods of this invention, the number of CD4 and / or CD8 T cells is elevated relative to prior to administration of the combination. In some embodiments of the methods of this invention, the number of activated CD4 and / or CD8 T cells is elevated relative to prior to administration of the combination. In some embodiments of the methods of this invention, activated CD4 and / or CD8 T cells are characterized by γ-IFN-producing CD4 and / or CD8 T cells and / or by enhanced cytolytic activity relative to prior to administration of the combination. In some embodiments of the methods of this invention, CD4 and / or CD8 T cells exhibit increased release of cytokines selected from the group consisting of IFN-γ, TNF-α, and interleukins. In some embodiments of the methods of this invention, the CD4 and / or CD8 T cell is an effector memory T cell. In some embodiments of the methods of this invention, the effector memory CD4 and / or CD8 T cell is characterized by γ-IFN producing CD4 and / or CD8 T cells and / or by enhanced cytolytic activity. In some embodiments of the methods of this invention, the effector memory CD4 and / or CD8 cell Y is characterized as having CD44highCD62Llow expression. In some embodiments of the methods of this invention, the cancer has high levels of T cell infiltration. In some embodiments, the methods of the invention may further comprise the administration of additional therapy. Additional therapy may be radiation therapy, surgery, chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the above. The additional therapy may be in the form of adjuvant or neo-adjuvant therapy. In some modalities, the additional therapy is the administration of side effect limiting agents (e.g., agents intended to decrease the occurrence and / or severity of side effects of treatment, such as anti-nausea agents). In some modalities, the additional therapy is radiation therapy. In some modalities, the additional therapy is surgery. In some embodiments, the additional therapy may be one or more of the chemotherapeutic agents described herein above. Any of the PD-1 axis binding antagonists that decrease or inhibit the expression and / or activity of TIGIT described below can be used in the methods of the invention. In some modalities, any of the targets described herein (e.g., PD-1, PD-L1, PDhQHQnn / Lznz / E / Yli - 70 L2, CTLA-4, LAG3, TIM3, BTLA, VISTA, B7H4, CD96, B7-1, TIGIT, CD226, OX-40, CD28, CD27, CD137, HVEM, GITR, MICA, ICOS, NKG2D, 2B4, etc.) is a human protein. PD-1 axis binding antagonists Provided herein is a method for treating or delaying the progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression of PD-1. and / or the activity of TIGIT. Also provided herein is a method of reducing or inhibiting cancer recurrence or cancer progression in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. Also provided herein is a method of treating or slowing the progression of an immune-related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. Also provided herein is a method of reducing or inhibiting the progression of an immune-related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. Also provided herein is a method of increasing, improving or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. For example, a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist, and a PD-L2 binding antagonist. In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its ligand binding partners. In a specific aspect the ligand binding partners of PD-1 are PD-L1 and / or PD-L2. In another embodiment, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, PD-L1 binding partners are PD-1 and / or B7-1. In another embodiment, the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partners. In a specific aspect, a binding partner of PD-L2 is PD-1. The antagonist can be an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide. In some embodiments, the PD-1 binding antagonist is selected from MDX-1106 (nivolumab), Merck 3745 (lambrolizumab), CT-011 (pidilizumab), and AMP-224. In some embodiments, the PDL1 binding antagonist is selected from YW243.55.S70, MPDL3280A, MDX-1105, and MEDI 4736. In some embodiments, the PD-L2 binding antagonist is AMP-224. In some embodiments, the PD-1 binding antagonist is AMP-224. MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO2007 / 005874. The YW243.55.S70 antibody (SEQ ID No. 20) is an anti-PD-L1 antibody described in WO 2010 / 077634 A1 and US 8,217,149, which are incorporated herein by reference. MDX-1106, also known as MDX-1106-04, ONO-4538, BMS-936558, or nivolumab, is an anti-PD-1 antibody described in WO2006 / 121168. The Merck 3745, also hQHQnn / Lznz / E / Yli - 71 known as MK 3475, MK-3475, SCH-900475, or lambrolizumab, is an anti-PD-1 antibody described in WO2009 / 114335. CT-011, also known as hBAT, hBAT-1, or pidilizumab, is an anti-PD-1 antibody described in WO2009 / 101611. AMP-224, also known as B7-DCIg, is a soluble receptor PD-L2-Fc fusion described in WO2010 / 027827 and WO2011 / 066342. Examples of anti-PD-L1 antibodies useful for the methods of this invention, and methods for their production, are described in PCT patent application WO 2010 / 077634 A1 and US 8,217,149, which are incorporated herein by reference. In some embodiments, the PD-1 axis binding antagonist is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody has the ability to inhibit binding between PD-L1 and PD-1 and / or between PD-L1 and B7-1. In some embodiments, the anti-PD-L1 antibody is a monoclonal antibody. In some embodiments, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fabj2) fragments. In some embodiments, the anti-PD-L1 antibody is a humanized antibody In some embodiments, the anti-PD-L1 antibody is a human antibody. The anti-PD-L1 antibodies useful in this invention, including compositions containing such antibodies, such as those described in WO 2010 / 077634 A1 and US 8,217,149, can be used in combination with an agent that decreases or inhibits the expression and / or or the activity of TIGIT with or without any additional therapy (e.g., chemotherapy) to treat cancer or an immune-related disease (e.g., T-cell dysfunctional disorder, viral infection, chronic viral infection, etc.). In one embodiment, the anti-PD-L1 antibody contains a heavy chain variable region polypeptide comprising a HVR-H1, HVR-H2, and HVR-H3 sequence, wherein: (a) the HVR-H1 sequence is GFTFSX1SWIH (SEQ ID NO: 33); (b) the sequence HVR-H2 s AWIX2PYGGSX3YYADSVKG (SEQ ID NO: 34); (c) the HVR-H3 sequence is RHWPGGFDY (SEQ ID NO: 19); further where: Xi is D or G; X2 is S or L; X3 is T or S. In a specific aspect, X1 is D; X2 is S and X3 is T. In another aspect, the polypeptide further comprises juxtaposed variable region heavy chain framework sequences between the HVRs according to the formula (HC-FR1)-(HVR-H1)-(HC-FR2 )-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4). In yet another aspect, the framework sequences are derived from human consensus framework sequences. In a further aspect, the framework sequences are VH subgroup III consensus frameworks. In a still further aspect, at least one of the structure sequences is as follows: HC-FR1 is EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 25) HC-FR2 is WVRQAPGKGLEWV (SEQ ID NO: 26) HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 27) HC-FR4 is WGQGTLVTVSA (SEQ ID NO: 28). In a still further aspect, the heavy chain polypeptide is further combined with a variable region hQHQnn / Lznz / E / Yli light chain comprising an HVR-L1, HVR-L2 and HVR-L3, wherein: (a) the HVR-L1 sequence is RASQX4X5X6TX7X8A (SEQ ID NO: 35); (b) the HVR-L2 sequence is SASX9LX10S (SEQ ID NO: 36); (c) the HVR-L3 sequence is QQX11X12X13X14PX15T (SEQ ID NO: 37); further where: X4 is D or V; X5 is V or I; Xe is S or N; X7 is A or F; Xs is V or L; Xg is F or T; Xw is Y or A; X11 is Y, G, F, or S; X12 is L, Y, F, or W; X13 is Y, N, A, T, G, F, or I; X14 is Η, V, P, T or I; Xw is A, W, R, P, or T. In yet another aspect, X4 is D; X5 is V; X6 is S; X7 is A; X8 is V; X9 is F; X10 is Y; X11 is Y; X12 is L; X13 is Y; X14 is Η; X15 is A. In a still further aspect, the light chain further comprises juxtaposed variable region light chain framework sequences between the HVRs according to the formula (LC-FR1)-(HVR-L1)-(LC-FR2) -(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In a still further aspect, the framework sequences are derived from human consensus framework sequences. In a still further aspect, the framework sequences are the consensus kappa I framework of VL. In a still further aspect, at least one of the structure sequences is as follows: LC-FR1 is DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 29) LC-FR2 is WYQQKPGKAPKLLIY (SEQ ID NO: 30) LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 31) LC-FR4 is FGQGTKVEIKR (SEQ ID NO: 32). In another embodiment, an isolated anti-PD-L1 antibody or antigen-binding fragment is provided comprising a heavy chain and a light chain variable region sequence, wherein: (a) the heavy chain comprises a HVR-H1, HVR-H2 and HVR-H3, where further: (i) the HVR-H1 sequence is GFTFSX1SWIH; (SEQ ID NO: 33) (ii) the HVR-H2 sequence is AWIX2PYGGSX3YYADSVKG (SEQ ID NO: 34) (iii) the HVR-H3 sequence is RHWPGGFDY, (SEQ ID NO: 19) and (b) the light chain includes an HVR-L1, HVR-L2 and HVR-L3, where in addition: (i) the HVR-L1 sequence is RASQX4X5X6TX7X8A (SEQ ID NO: 35) (ii) the HVR-L2 sequence is SASX9LX10S (SEQ ID NO: 36); and (iii) the HVR-L3 sequence is QQX11X12X13X14PX15T; (SEQ ID NO: 37) further wherein: X-i is D or G; X2 is S or L; X3 is T or S; X4 is D or V; X5 is V or I; X6 is Y or N; X? is A or F; X8 is V or L; X9 is F or T; Xw is Y or A; Xn is Y, G, F, or S; X12 is L, Y, F, or W; X13 is Y, N, A, T, G, F, or I; X14 is Η, V, P, Το I; Xwes A, W, R, PoT. In a specific aspect, X1 is D; X2 is S and X3 is T. In another aspect, X4 is D; X5 is V; Xe is S; X7 is A; X8 is V; Xg is F; Xw is Y; Xn is Y; X12 is L; Xw is Y; X14 is H; Xw is A. In yet another aspect, X1 is D; X2 is S and X3 is T, X4 is D; Xses V; Xe is S; X7 is A; Xs is V; Xg is F; XwesY; Xn is Y; Xi2 is L; XwesY; X14 is H and Xwes A. In a further aspect, the heavy chain variable region comprises one or more juxtaposed framework sequences between the HVRs such as: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC -FR3)-(HVR-H3)-(HC-FR4), frannon / Lznz / E / YL - 73 and light chain variable regions comprise one or more backbone sequences juxtaposed between HVRs such as: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3 )-(HVR-L3)-(LC-FR4). In a still further aspect, the framework sequences are derived from human consensus framework sequences. In a still further aspect, the heavy chain framework sequences are derived from a subgroup I, II or III Kabat sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is as follows: HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 25) HC-FR2 WVRQAPGKGLEWV (SEQ ID NO: 26) HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 27) HC-FR4 WGQGTLVTVSA (SEQ ID NO: 28). In a still further aspect, the light chain framework sequences are derived from a kappa subgroup I, II, III or IV Kabat sequence. In a still further aspect, the light chain framework sequences are the consensus kappa I framework of VL. In yet a further aspect, one or more of the light chain framework sequences is as follows: LC-FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 29) LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 30) LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 31) LC-FR4 FGQGTKVEIKR (SEQ ID NO: 32). In a yet further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In a yet further specific aspect, the human constant region is lgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region is lgG2A. In yet a further specific aspect, the antibody has reduced or minimal effector function. In yet a further specific aspect the minimal effector function results from a "Fe no effector mutation" or aglycosylation. In yet a further embodiment, the Fc non-effector mutation is an N297A or D265A / N297A substitution in the constant region. In yet another embodiment, an anti-PD-L1 antibody is provided comprising a heavy chain and a light chain variable region sequence, wherein: (a) the heavy chain further comprises a HVR-H1, HVR-H2 and a HVR-H3 sequence having at least 85% sequence identity to GFTFSDSWIH (SEQ ID NO: 17), AWISPYGGSTYYADSVKG (SEQ ID NO: 18) and RHWPGGFDY (SEQ ID NO: 19), respectively, or (b) the light chain further comprises an HVR-L1, HVR-L2, and an HVR-L3 sequence having at least 85% sequence identity to RASQDVSTAVA (SEQ ID NO: 20), SASFLYS (SEQ ID NO: 21) and QQYLYHPAT (SEQ ID NO: 22), respectively. (c) In a specific aspect, the sequence identity is 86%, 87%, 88%, 89%, 90%, 91%, hQHQnn / L7R7 / B / YI - 74 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. In another aspect, the heavy chain variable region comprises one or more juxtaposed framework sequences between the HVRs such as: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HCFR3) -(HVR-H3)-(HC-FR4), and light chain variable regions comprise one or more juxtaposed backbone sequences between the HVRs such as: (LC-FR1)-(HVR-L1)-(LC-FR2) -(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In yet another aspect, the framework sequences are derived from human consensus framework sequences. In a still further aspect, the heavy chain framework sequences are derived from a subgroup I, II or III Kabat sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is as follows: HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 25) HC-FR2 WVRQAPGKGLEWV (SEQ ID NO: 26) HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 27) HC-FR4 WGQGTLVTVSA (SEQ ID NO: 28). In a still further aspect, the light chain framework sequences are derived from a kappa subgroup I, II, III or IV Kabat sequence. In a still further aspect, the light chain framework sequences are the consensus kappa I framework of VL. In yet a further aspect, one or more of the light chain framework sequences is as follows: LC-FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 29) LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 30) LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 31) LC-FR4 FGQGTKVEIKR (SEQ ID NO: 32). In a yet further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In a yet further specific aspect, the human constant region is lgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region is lgG2A. In yet a further specific aspect, the antibody has reduced or minimal effector function. In yet a further specific aspect the minimal effector function results from a "Fe no effector mutation" or aglycosylation. In yet a further embodiment, the Fc non-effector mutation is an N297A or D265A / N297A substitution in the constant region. In yet a further embodiment, an isolated anti-PD-L1 antibody is provided comprising a heavy chain and a light chain variable region sequence, wherein: (a) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO: 23), - 75 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTK (SEQ ID NO: 40), or EvqlvesgggggggggslrlscaasgftfsDSwihwvrqapgKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAEDTAVYYCARRHWPGFDYWGQGTLVTVSS sequence for light chain sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 24). In a specific aspect, the sequence identity is 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. In another aspect, the heavy chain variable region comprises one or more juxtaposed framework sequences between the HVRs such as: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC- FR3)(HVR-H3)-(HC-FR4), and light chain variable regions comprise one or more juxtaposed backbone sequences between the HVRs such as: (LC-FR1)-(HVR-L1)-(LC-FR2 )-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In yet another aspect, the framework sequences are derived from human consensus framework sequences. In a further aspect, the heavy chain framework sequences are derived from a subgroup I, II or III Kabat sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is as follows: HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 25) HC-FR2 WVRQAPGKGLEWV (SEQ ID NO: 26) HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 27) HC-FR4 WGQGTLVTVSA (SEQ ID NO: 28). In a still further aspect, the light chain framework sequences are derived from a kappa subgroup I, II, III or IV Kabat sequence. In a still further aspect, the light chain framework sequences are the consensus kappa I framework of VL. In yet a further aspect, one or more of the light chain framework sequences is as follows: LC-FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 29) LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 30) LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 31) LC-FR4 FGQGTKVEIKR (SEQ ID NO: 32). In a yet further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In a yet further specific aspect, the human constant region is lgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region is lgG2A. In yet a further specific aspect, the antibody has reduced or minimal effector function. In yet another specific aspect, the minimal effector function - 76 results from production in prokaryotic cells. In yet a further specific aspect the minimal effector function results from a non-effector "Fe" mutation or aglycosylation. In yet a further embodiment, the Fc non-effector mutation is an N297A or D265A / N297A substitution in the constant region. In yet a further embodiment, the invention provides compositions comprising any of the above-described anti-PD-L1 antibodies in combination with at least one pharmaceutically acceptable carrier. In yet a further embodiment, an isolated nucleic acid encoding an anti-PD-L1 antibody heavy or light chain variable region sequence is provided, wherein: (a) the heavy chain further comprises a HVR-H1, HVR-H2 and a HVR-H3 sequence having at least 85% sequence identity to GFTFSDSWIH (SEQ ID NO: 17), AWISPYGGSTYYADSVKG (SEQ ID NO: 18) and RHWPGGFDY (SEQ ID NO: 19), respectively, and (b) the light chain further comprises an HVR-L1, HVR-L2, and an HVR-L3 sequence having at least 85% sequence identity to RASQDVSTAVA (SEQ ID NO: 20), SASFLYS (SEQ ID NO: 21) and QQYLYHPAT (SEQ ID NO: 22), respectively. In a specific aspect, the sequence identity is 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. In one aspect, the heavy chain variable region comprises one or more juxtaposed framework sequences between the HVRs such as: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC- FR3)(HVR-H3)-(HC-FR4), and light chain variable regions comprise one or more juxtaposed backbone sequences between the HVRs such as: (LC-FR1)-(HVR-L1)-(LC-FR2 )-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In yet another aspect, the framework sequences are derived from human consensus framework sequences. In a further aspect, the heavy chain framework sequences are derived from a subgroup I, II or III Kabat sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is as follows: HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 25) HC-FR2 WVRQAPGKGLEWV (SEQ ID NO: 26) HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 27) HC-FR4 WGQGTLVTVSA (SEQ ID NO: 28). In a still further aspect, the light chain framework sequences are derived from a kappa subgroup I, II, III or IV Kabat sequence. In a still further aspect, the light chain framework sequences are the consensus kappa I framework of VL. In yet a further aspect, one or more of the light chain framework sequences is as follows: LC-FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 29) LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 30) LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 31) LC-FR4 FGQGTKVEIKR (SEQ ID NO: 32). In yet a further specific aspect, the antibody further comprises an hQHQnn / Lznz / E / Yli constant region - 77 human or murine. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In yet a further specific aspect, the human constant region is lgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region is lgG2A. In yet a further specific aspect, the antibody has reduced or minimal effector function. In yet a further specific aspect, minimal effector function results from production in prokaryotic cells. In yet a further specific aspect the minimal effector function results from a "Fe no effector mutation" or aglycosylation. In a still further aspect, the Fe no-effector mutation is an N297A or D265A / N297A substitution in the constant region. In yet another embodiment, an isolated anti-PDL1 antibody is provided comprising a heavy chain and a light chain variable region sequence, wherein: (a) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 41), or (b) the light chain sequences have at least 85% sequence identity to the light chain sequence : DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 24). In a specific aspect, the sequence identity is 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. In another aspect, the heavy chain variable region comprises one or more juxtaposed framework sequences between the HVRs such as: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC- FR3)(HVR-H3)-(HC-FR4), and light chain variable regions comprise one or more juxtaposed backbone sequences between the HVRs such as: (LC-FR1)-(HVR-L1)-(LC-FR2 )-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In yet another aspect, the framework sequences are derived from human consensus framework sequences. In a further aspect, the heavy chain framework sequences are derived from a subgroup I, II or III Kabat sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is as follows: HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 25) HC-FR2 WVRQAPGKGLEWV (SEQ ID NO: 26) HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 27) HC-FR4 WGQGTLVTVSS (SEQ ID NO: 42). In a still further aspect, the light chain framework sequences are derived from a kappa subgroup I, II, III or IV Kabat sequence. In a still further aspect, the light chain framework sequences are the consensus kappa I framework of VL. In yet a further aspect, one or more of the light chain framework sequences is as follows: hanonn / 1 znz / E / Yl· LC-FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 29) LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 30) LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 31) LC-FR4 FGQGTKVEIKR (SEQ ID NO: 32). In yet a further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In yet a further specific aspect, the human constant region is lgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region is lgG2A. In yet a further specific aspect, the antibody has reduced or minimal effector function. In yet a further specific aspect, minimal effector function results from production in prokaryotic cells. In yet a further specific aspect the minimal effector function results from a "Fe no effector mutation" or agicosylation. In yet a further embodiment, the Fc non-effector mutation is an N297A or D265A / N297A substitution in the constant region. In a further aspect, the heavy chain variable region comprises one or more juxtaposed framework sequences between the HVRs such as: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC -FR3)-(HVR-H3)-(HC-FR4), and light chain variable regions comprise one or more juxtaposed backbone sequences between the HVRs such as: (LC-FR1)-(HVR-L1)-(LC -FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In a still further aspect, the framework sequences are derived from human consensus framework sequences. In a still further aspect, the heavy chain framework sequences are derived from a subgroup I, II or III Kabat sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is as follows: HC-FR1 EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 43) HC-FR2 WVRQAPGKGLEWVA (SEQ ID NO: 44) HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 27) HC-FR4 WGQGTLVTVSS (SEQ ID NO: 45). In a still further aspect, the light chain framework sequences are derived from a kappa subgroup I, II, III or IV Kabat sequence. In a still further aspect, the light chain framework sequences are the consensus kappa I framework of VL. In yet a further aspect, one or more of the light chain framework sequences is as follows: LC-FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 29) LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 30) LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 31) LC-FR4 FGQGTKVEIK (SEQ ID NO: 46). In yet a further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of franonn / Lznz / E / YL - 79 lgG1, lgG2, lgG2, lgG3, lgG4. In yet a further specific aspect, the human constant region is lgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region is lgG2A. In yet a further specific aspect, the antibody has reduced or minimal effector function. In yet a further specific aspect the minimal effector function results from a non-effector Fe' mutation or agicosylation. In yet a further embodiment, the Fc non-effector mutation is an N297A or D265A / N297A substitution in the constant region. In yet another embodiment, an anti-PDL1 antibody is provided comprising a heavy chain and a light chain variable region sequence, wherein: (d) the heavy chain further comprises an HVR-H1, HVR-H2 and an HVR-H3 sequence having at least 85% sequence identity to GFTFSDSWIH (SEQ ID NO: 17), AWISPYGGSTYYADSVKG (SEQ ID NO: 18) and RHWPGGFDY (SEQ ID NO: 19), respectively, or (e) the light chain further comprises an HVR-L1, HVR-L2, and an HVR-L3 sequence having at least 85% sequence identity to RASQDVSTAVA (SEQ ID NO: 20), SASFLYS (SEQ ID NO: 21) and QQYLYHPAT (SEQ ID NO: 22), respectively. In a specific aspect, the sequence identity is 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. In another aspect, the heavy chain variable region comprises one or more juxtaposed framework sequences between the HVRs such as: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC- FR3)(HVR-H3)-(HC-FR4), and light chain variable regions comprise one or more juxtaposed backbone sequences between the HVRs such as: (LC-FR1)-(HVR-L1)-(LC-FR2 )-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In yet another aspect, the framework sequences are derived from human consensus framework sequences. In a still further aspect, the heavy chain framework sequences are derived from a subgroup I, II or III Kabat sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is as follows: HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 25) HC-FR2 WVRQAPGKGLEWV (SEQ ID NO: 26) HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 27) HC-FR4 WGQGTLVTVSSASTK (SEQ ID NO: 47). In a still further aspect, the light chain framework sequences are derived from a kappa subgroup I, II, III or IV Kabat sequence. In a still further aspect, the light chain framework sequences are the consensus kappa I framework of VL. In yet a further aspect, one or more of the light chain framework sequences is as follows: LC-FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 29) LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 30) LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 31) hQHQnn / L7R7 / B / YI LC-FR4 FGQGTKVEIKR (SEQ ID NO: 32). In yet a further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In yet a further specific aspect, the human constant region is lgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region is lgG2A. In yet a further specific aspect, the antibody has reduced or minimal effector function. In yet a further specific aspect minimal effector function results from a "Fe no effector mutation" or agicosylation. In yet a further embodiment, the Fc non-effector mutation is an N297A or D265A / N297A substitution in the constant region. In yet a further embodiment, an isolated anti-PDL1 antibody is provided comprising a heavy chain and a light chain variable region sequence, wherein: (a) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTK (SEQ ID NO: 40), or (b) the light chain sequences have at least 85% sequence identity to the sequence light chain: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 24). In some embodiments, an isolated anti-PDL1 antibody is provided comprising a heavy chain and a light chain variable region sequence, wherein the light chain variable region sequence is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 24. In some embodiments, an isolated anti-PDL1 antibody is provided that comprises a variable region sequence of heavy chain and one of light chain, wherein the heavy chain variable region sequence is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity for the amino acid sequence of SEQ ID NO: 40. In some embodiments, an isolated anti-PDL1 antibody is provided comprising a heavy chain and a light chain variable region sequence, wherein the light chain variable region sequence has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94% , at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity for the amino acid sequence of SEQ ID NO: 24 and the chain variable region sequence heavy has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, al hanonn / i zoz / e / yl - At least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity for the amino acid sequence of SEQ ID NO: 40. In yet a further embodiment, an isolated anti-PDL1 antibody is provided comprising a heavy chain and a light chain sequence, wherein: (a) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 48), or (b) the light chain sequences have at least 85% sequence identity to the light chain sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 49). In some embodiments, an isolated anti-PDL1 antibody is provided comprising a heavy chain and a light chain sequence, wherein the light chain sequence is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity for the amino acid sequence of SEQ ID NO: 49. In some embodiments, an isolated anti-PDL1 antibody is provided comprising a heavy chain and a light chain sequence, wherein the heavy chain sequence is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 48. In some embodiments, an isolated anti-PDL1 antibody is provided comprising a heavy chain and a light chain sequence, wherein the light chain sequence is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity for the amino acid sequence of SEQ ID NO: 49 and the heavy chain sequence is at least 85%, at least 86%, at least 87%, at least 88% , at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% , or at least 99% sequence identity for the amino acid sequence of SEQ ID NO: 48. In a still further aspect, the nucleic acid further comprises a suitable vector for the hanonn / ι znz / E / Yl· - 82 expression of the nucleic acid encoding any of the previously described anti-PD-L1 antibodies. In yet a further specific aspect, the vector further comprises a host cell suitable for expression of the nucleic acid. In yet a further specific aspect, the host cell is a eukaryotic cell or a prokaryotic cell. In yet a further specific aspect, the eukaryotic cell is a mammalian cell, such as a Chinese hamster ovary (CHO). The anti-PD-L1 antibody or antigen-binding fragment thereof, can be produced using methods known in the art, for example, by a process comprising culturing a host cell containing the nucleic acid encoding any of the anti-PD-L1 antibodies. - previously described PD-L1 or antigen-binding fragment in a form suitable for expression, under conditions suitable for producing such antibody or fragment, and recovering the antibody or fragment. In yet a further embodiment, the invention provides a composition comprising an anti-PD-L1 antibody or antigen-binding fragment thereof as provided herein and at least one pharmaceutically acceptable carrier. Agents that decrease or inhibit the expression and / or activity of TIGIT Provided herein is a method of treating or slowing the progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or TIGIT activity. Also provided herein is a method of reducing or inhibiting cancer recurrence or cancer progression in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. Also provided herein is a method of treating or slowing the progression of an immune-related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. Also provided herein is a method of reducing or inhibiting the progression of an immune-related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. Also provided herein is a method of increasing, improving or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits the expression and / or activity of TIGIT. Also provided herein is a method of increasing, improving or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent that decreases or inhibits one or more co-inhibitory receptors of additional immunity. Also provided herein is a method of increasing, improving or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of an agent that decreases or inhibits the expression and / or activity of TIGIT and an agent that increases or activates one or more additional immune co-stimulatory receptors. For example, the agent who hanonn / i zoz / e / yl - 83 decreases or inhibits the expression and / or activity of TIGIT includes an antagonist of the expression and / or activity of TIGIT, an antagonist of the expression and / or activity of PVR, an agent that inhibits and / or blocks the interaction of TIGIT with PVR, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL2, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL3, an agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR, an agent that inhibits and / or blocks intracellular signaling mediated by binding of TIGIT to PVRL2, an agent that inhibits and / or blocks intracellular signaling mediated by binding of TIGIT to PVRL3, and combinations of the themselves. In some embodiments, the antagonist of TIGIT expression and / or activity includes a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the antagonist of PVR expression and / or activity includes a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks the interaction of TIGIT with PVR includes a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. . In some embodiments, the agent that inhibits and / or blocks the interaction of TIGIT with PVRL2 includes a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. . In some embodiments, the agent that inhibits and / or blocks the interaction of TIGIT with PVRL3 includes a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. . In some embodiments, the agent that inhibits and / or blocks intracellular signaling mediated by the binding of TIGIT to PVR includes a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid , and an inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks intracellular signaling mediated by TIGIT binding to PVRL2 includes a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid , and an inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks intracellular signaling mediated by TIGIT binding to PVRL3 includes a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid , and an inhibitory polypeptide. In some embodiments, the antagonist of TIGIT expression and / or activity is an inhibitory nucleic acid selected from an antisense polynucleotide, an interfering RNA, a catalytic RNA, and an RNA-DNA chimera. hanonn / i zoz / e / yl In some embodiments, the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody. - 84 TIGIT or an antigen-binding fragment thereof. Anti-TIGIT antibodies useful in this invention, including compositions containing such antibodies, such as those described in WO 2009 / 126688, can be used in combination with PD-1 axis-binding antagonists. Anti-TIGIT antibodies The present invention provides anti-TIGIT antibodies. Exemplary antibodies include polyclonal, monoclonal, humanized, bispecific, and heteroconjugate antibodies. It will be understood by those of ordinary skill in the art that the invention also provides antibodies against other polypeptides (i.e., anti-PVR antibodies) and that any part of the description herein directed specifically to the method of creation, production, varieties, use or other aspects of anti-TIGIT antibodies will also be applicable to antibodies specific for other non-TIGIT polypeptides. polyclonal antibodies Anti-TIGIT antibodies may comprise polyclonal antibodies. Methods for preparing antibodies are known to the skilled artisan. Polyclonal antibodies can be raised in a mammal, for example, by means of one or more injections of an immunizing agent and, if desired, an adjuvant. Typically, the immunizing agent and / or adjuvant will be injected into the mammal via multiple subcutaneous or intraperitoneal injections. The immunizing agent can include the TIGIT polypeptide or a fusion protein thereof. It may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include, but are not limited to, limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. Examples of the adjuvants that can be employed include Freund's complete adjuvant and MPL-TDM adjuvant (monophosphoryl lipid A, synthetic trehalose dicorynomycolate). The immunization protocol can be selected by one of skill in the art without undue experimentation. Monoclonal antibodies Alternatively, the anti-TIGIT antibodies can be monoclonal antibodies. Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Millstein, Nature 256: 495 (1975). In a hybridoma method, typically a mouse, hamster, or other appropriate host animal is immunized with an immunizing agent to obtain lymphocytes that produce or have the ability to produce antibodies that will specifically bind to the immunizing agent. Alternatively, lymphocytes can be immunized in vitro. The immunizing agent will typically include the TIGIT polypeptide or a fusion protein thereof. Generally, either peripheral blood lymphocytes ("PBLs'j) are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with a cell line immortalized using a suitable fusion agent, such as polyethylene glycol, to form a hybridoma cell [Goding, Monoclonal Antibodies: Principles and Practice hQHQnn / Lznz / E / Yli - 85 (Monoclonal Antibodies: Principles and Practice), Academic Press, (1986) pp. 59-103], Immortalized cell lines are commonly transformed mammalian cells, particularly rodent, bovine, and human myeloma cells. Rat or mouse myeloma cell lines are commonly employed. The hybridoma cells can be grown in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused immortalized cells. For example, if the cells of origin lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for hybridomas will typically include hypoxanthine, aminopterin, and thymidine ("HAY medium"), substances that prevent the growth of hybridomas. HGPRT-deficient cells. Preferred immortalized cell lines are those that fuse efficiently, support stable high-level expression of the antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. The most preferred immortalized cell lines are murine myeloma lines, which can be obtained, for example, from the Salk Institute Cell Distribution Center, San Diego, California and from the American Type Culture Collection, Mannassas, Virginia. Human myeloma and human mouse heteromyeloma cell lines have also been described for the production of human monoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63], The culture medium in which the hybridoma cells are grown can then be tested for the presence of monoclonal antibodies directed against the polypeptide. Preferably, the binding specificity of the monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques and analyzes are known in the art. For example, the binding affinity of the monoclonal antibody can be determined by the Scatchard assay of Munson and Pollard, Anal. Biochem., 107: 220 (1980). After the desired hybridoma cells are identified, clones can be subcloned by limiting dilution procedures and grown by standard methods [Goding, supra]. Suitable culture medium for this purpose include, for example, Dulbecco's modified Eagle's medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal. The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. Monoclonal antibodies can also be produced by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using standard procedures (e.g., using oligonucleotide probes with the ability to specifically bind to genes encoding murine antibody heavy and light chains). The hybridoma cells of the invention serve as a preferred source of hQHQnn / Lznz / E / Yli - 86 such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or otherwise non-producing myeloma cells. the immunoglobulin protein, to obtain the synthesis of the monoclonal antibodies in the recombinant host cells. The DNA can also be modified, for example, by substituting the coding sequence for the human heavy and light chain constant domains in place of the homologous murine sequences [U.S. Pat. No. 4,816,567; Morrison et al., supra] or by covalently linking to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such non-immunoglobulin polypeptide may be substituted for the constant domains of an antibody of the invention or may be substituted for the variable domains of an antigen combining site of an antibody of the invention to create a chimeric bivalent antibody. The antibodies can be monovalent antibodies. Methods for preparing monovalent antibodies are well known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and modified heavy chain. The heavy chain is generally truncated at any point in the Fe region in order to prevent crosslinking of the heavy chain. Alternatively, the relevant tanker residues are substituted with another amino acid residue or deleted in order to avoid crosslinking. In vitro methods for preparing monovalent antibodies are also suitable. Digestion of antibodies to produce fragments thereof, particularly Fab fragments, can be carried out using routine techniques known in the art. Human and humanized antibodies The anti-TIGIT antibodies of the invention may further comprise humanized antibodies or human antibodies. Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab', F(abj2, or other antigen-binding antibody subsequences) that contain minimal sequence derived from non-human immunoglobulin Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementarity determining region (CDR) of the receptor are replaced by residues from a CDR from a non-human species (antibody donor) such as mouse, rat, or rabbit, which has the desired specificity, affinity, and capacity In some cases, the Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues Humanized antibodies may also comprise residues not found in the recipient antibody or in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains in which all or substantially all of the CDR regions correspond to those of a human immunoglobulin consensus sequence. The humanized antibody optimally will also comprise at least a portion of an immunoglobulin (Fe) constant region, typically that of a human immunoglobulin [ Jones et al., Nature, 321:522-525 (1986 ); Riechmann et al., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)]. hQHQnn / Lznz / E / Yli - 87 Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a non-human source. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain. Humanization can be carried out essentially following the method of Winter et al. [Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)] by substituting the rodent CDRs or CDR sequences for the corresponding sequences from a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (U.S. Patent No. 4,816,567), wherein substantially less than one intact human variable domain has been replaced by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are replaced by residues from analogous sites in rodent antibodies. Human antibodies can also be produced using a number of techniques known in the art including phage display libraries [Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)]. The techniques of Colé et al., and Boerner et al., for the preparation of human monoclonal antibodies are also available (Colé et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, 77 (1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991).] Similarly, human antibodies can be produced by introducing human immunoglobulin sites into transgenic animals, e.g., mice in which endogenous immunoglobulin genes have been partially or completely inactivated Upon challenge, human antibody production is observed that closely resembles that seen in humans in all respects including gene rearrangement, assembly, and repertoire This procedure is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the following scientific publications: Marks et al., Bio / Technology 10, 779-783 (1992); Lonberg et al., Nature 368 856-859 (1994); Morrison, Nature 368, 812-13 (1994); Fishwild et al., Nature Biotechnology 14, 845-51 (1996); Neuberger, Nature Biotechnology 14, 826 (1996); Lonberg and Huszar, Intern. Rev. Immunol. 13 65-93 (1995). Antibodies can also be affinity matured using known methods of selection and / or mutagenesis as described above. Preferred affinity matured antibodies have an affinity five times, more preferably 10 times, even more preferably 20 or 30 times greater than that of the starting antibody (generally murine, humanized or human) from which the matured antibody is prepared. bispecific antibodies Bispecific antibodies are monoclonal antibodies, preferably human or humanized, that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for TIGIT, the other is for any other antigen, and preferably for a cell surface protein or receptor or receptor subunit. hQDQnn / L7R7 / B / YI - 88 Methods for producing bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy chain / light chain pairs, where the two heavy chains have different specificities [Milstein and Cuello, Nature, 305: 537-539 (1983). )]. Due to the random selection of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules of which only one has the correct bispecific structure. Purification of the correct molecule is commonly carried out by affinity chromatography steps. Similar procedures are described in WO 93 / 08829, published May 13, 1993, and in Traunecker et al., EMBO. J., 10: 3655-3659 (1991). Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion is preferably with an immunoglobulin heavy chain constant domain, comprising at least part of the CH2 and CH3 hinge regions. It is preferable that the first heavy chain constant region (CH1) contains the necessary site for binding to the light chain present in at least one of the fusions. DNAs encoding immunoglobulin heavy chain and, if desired, immunoglobulin light chain fusions are inserted into separate expression vectors and co-transfected into a suitable host organism. For additional details of the generation of bispecific antibodies see, eg, Suresh et al., Methods in Enzymology, 121:210 (1986). According to another procedure described in WO 96 / 27011, the interlink between a pair of antibody molecules can be made to maximize the percentage of heterodimers that are recovered from recombinant cell culture. The preferred interlink comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interlink of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). Compensatory ''cavities'' of an identical or similar size to the large chain(s) are created on the interconnection of the second antibody molecule by replacing the large amino acid side chains with smaller ones (e.g. , alanine or threonine). This provides a mechanism to increase the production of the heterodimer over other unwanted end products such as homodimers. Bispecific antibodies can be prepared as full-length antibodies or antibody fragments (e.g., F(abj2) bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical bonding Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are cleaved proteolytically to generate F(abj2 fragments. These fragments are reduced in the presence of the complexing agent sodium dithiol arsenite to stabilize neighboring dithiols and prevent intermolecular disulfide formation.The generated Fab' fragments are then converted to thionitrobenzoate (TNB) derivatives.One of the TNB derivatives of Fab' is then reconverted to the Fab' thiol by reduction with mercaptoethylamine and mixed with an equimolar amount of the other TNB derivative of Fab' to form the antibody hQHQnn / L7R7 / B / YI - 89 bispecific. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes. Fab' fragments can be recovered directly from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med., 175: 217-225 (1992) describe the production of a fully immunized bispecific antibody F(abj2) molecule. Each Fab' fragment was separately secreted from E. coli and subjected to targeted chemical coupling in vitro to form the bispecific antibody.The bispecific antibody thus formed had the ability to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as to trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets. Various techniques for producing and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol., 148(5): 1547-1553 (1992). Leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. Antibody homodimers were reduced in the ligation region to form monomers and then re-oxidized to form antibody heterodimers. This method can also be used for the production of antibody homodimers. Diabody technology" described by Hollinger et al., Proc. nati. Acad. Sel. EUA 90: 6444-6448 (1993) has provided an alternative mechanism for producing bispecific antibody fragments. The fragments comprise a heavy chain variable domain (Vh) connected to a light chain variable domain (VL) via a linker too short to allow pairing between the two domains on the same chain. Consequently, the VH and VL domains of one fragment are forced to pair with the Vl and Vh domains of another fragment, thus forming two antigen-binding sites. Another strategy to produce bispecific antibody fragments by using single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol., 152: 5368 (1994). Antibodies with more than two valences are contemplated. As a non-limiting example, trispecific antibodies can be prepared. See, e.g., Tutt et al., J. Immunol., 147: 60 (1991). Exemplary bispecific antibodies can bind to two different epitopes on a TIGIT polypeptide given herein. Alternatively, an anti-TIGIT polypeptide arm can be combined with an arm that binds to a trigger molecule on a leukocyte such as a T cell receptor molecule (e.g., CD2, CD3, CD28, or B7), or to Fe receptors for IgG ( FcyR), such as FcyRI (CD64), FcyRII (CD32), and FcyRIII (CD16) in order to target cellular defense mechanisms to the cell expressing the particular TIGIT polypeptide. Bispecific antibodies can also be used to localize cytotoxic agents in cells that express a particular TIGIT polypeptide. These antibodies possess an arm that binds to TIGIT and an arm that binds to a cytotoxic agent or radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds to the TIGIT polypeptide and further binds to tissue factor (RF). Heteroconjugate antibodies - 90 Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are made up of two covalently linked antibodies. For example, such antibodies have been proposed to target cells of the immune system to unwanted cells [U.S. Pat. No. 4,676,980] and for the treatment of HIV infection [WO 91 / 00360; WO 92 / 200373; EP 03089], It is contemplated that antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those described, for example, in U.S. Pat. No. 4,676,980. Effector function engineering It may be desirable to modify the antibody of the invention with respect to effector function in order to improve, e.g., the effectiveness of the antibody in the treatment of cancer. For example, a cysteine ​​residue(s) can be introduced into the Fe region, thus allowing interchain disulfide bond formation in this region. The homodimeric antibody so generated may have enhanced internalizing capacity and / or complement-mediated cell killing and increased antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional crosslinkers as described in Wolff et al. Cancer Research, 53: 2560-2565 (1993). Alternatively, an antibody can be made which has double Fc regions and thus may have enhanced ADCC and complement lysis capacity. See Stevenson et al., Anti-Cancer Drug Design 3:219-230 (1989). In some embodiment, anti-TIGIT antibodies were generated that were hamster anti-mouse antibodies. Two antibodies, 10A7 and 1F4, also specifically bound to human TIGIT. The amino acid sequences of the heavy and light chains of the 10A7 antibody were determined using standard techniques. The light chain sequence of this antibody is: DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO: 13) and the heavy chain sequence of this antibody is: EVQLVESGGG LTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFTISRDNAKNLLF LQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO: 15), wherein the complementarity determining regions (CDRs) of each string are represented by bold text. Thus, the 10A7 light chain CDR1 has the sequence KSSQSLYYSGVKENLLA (SEQ ID NO: 1), the 10A7 light chain CDR2 has the sequence ASIRFT (SEQ ID NO: 2), and the 10A7 light chain CDR3 has the sequence QQGINNPLT (SEQ ID NO: 3). The 10A7 heavy chain CDR1 has the sequence GFTFSSFTMH (SEQ ID NO: 4), the 10A7 heavy chain CDR2 has the sequence FIRSGSGIVFYADAVRG (SEQ ID NO: 5), and the 10A7 heavy chain CDR3 has the sequence RPLGHNTFDS (SEQ ID NO: 6). franconn / Lznz / E / YL - 91 The amino acid sequences of the light and heavy chains of the 1F4 antibody were also determined. The light chain sequence of this antibody is: DWLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGSGTDFTLKIS TIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO: 14) and the heavy chain sequence of this antibody is: EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLM NWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLTVDKSSSTAY MELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO: 16), wherein the complementarity determining regions (CDRs) of each chain are represented by text in bold font. Thus, 1F4 light chain CDR1 has the sequence RSSQSLVNSYGNTFLS (SEQ ID NO: 7), 1F4 light chain CDR2 has the sequence GISNRFS (SEQ ID NO: 8), and 1F4 light chain CDR3 has the sequence LQGTHQPPT (SEQ ID NO: 9). The 1F4 heavy chain CDR1 has the sequence GYSFTGHLMN (SEQ ID NO: 10), the 1F4 heavy chain CDR2 has the sequence LIIPYNGGTSYNQKFKG (SEQ ID NO: 11), and the 1F4 heavy chain CDR3 has the sequence GLRGFYAMDY (SEQ ID NO: 12). It was determined that the nucleotide sequence encoding the 1F4 light chain is GATGTTGTGTTGACTCAAACTCCACTCTCCCTGTCTGTCAGCTTTGGAGATCAAGTTTCTATCTCTTGCAGGTCTAGT CAGAGTCTTGTAAACAGTTATGGGAACACCTTTTTGTCTTGGTACCTGCACAAGCCTGGCCAGTCTCCACAGCTCCT CATCTTTGGGA TTTCCAACAGATTTTCTGGGGTGCCAGACAGGTTCAGTGGCAGTGGTTCAGGGACAGATTTCACAC TCAAGATCAGCACAATAAAGCCTGAGGACTTGGGAATGTATTACTGCTTACAAGGTACGCATCAGCCTCCCACGTTC GGTCCTGGGACCAAGCTGGAGGTGAAA (SEQ ID NO: 38) and it was determined that the nucleic sequence ótidos that codes for the heavy chain 1F4 is GAGGTCCAGCTGCAACAGTCTGGACCTGAGCTGGTGAAGCCTGGAACTTCAATGAAGATATCCTGCAAGGCTTCTG GTTACTCATTCACTGGCCATTCTTATGAACTGGGTGAAGCAGAGCCATGGAAAGAACCTTGAGTGGATTGGACTTATT ATTCCTTACAATGGTGGTACAAGCTATAACCAGAAGTTCAAGGGCAAGGCCA CATTGACTGTAGACAAGTCATCCAG CACAGCCTACATGGAGCTCCTCAGTCTGACTTCTGATGACTCTGCAGTCTATTTCTGTTCAAGAGGCCTTAGGGGCT TCTATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 39). In some embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof comprises at least one HVR comprising an amino acid sequence selected from the amino acid sequences set forth in (1) KSSQSLYYSGVKENLLA (SEQ ID NO: 1), ASIRFT (SEQ ID NO: 2), QQGINNPLT (SEQ ID NO: 3), GFTFSSFTMH (SEQ ID NO: 4), FIRSGSGIVFYADAVRG (SEQ ID NO: 5), and RPLGHNTFDS (SEQ ID NO: 6), or (2) RSSQSLVNSYGNTFLS (SEQ ID NO: 7), GISNRFS (SEQ ID NO: 8), LQGTHQPPT (SEQ ID NO: 9), GYSFTGHLMN (SEQ ID NO: 10), LIIPYNGGTSYNQKFKG (SEQ ID NO: 11), and GLRGFYAMDY (SEQ ID NO : 12). In some embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof, wherein the antibody light chain comprises the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLUYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO: 13) or DWLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLUFGISNRFSGVPDRFSGSGSGTDFTLKIS hQHQnn / Lznz / E / yli TIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO: 14). In some embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof, wherein the heavy chain of the antibody comprises the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRTISRDNAKNLLF LQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO : 15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLTVDKSSSTAY MELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO: 16). In some embodiments, the anti-TIGIT antibody or an antigen-binding fragment thereof, wherein the antibody light chain comprises the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLUYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO: 13) or DWLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGSGTDFTLKIS TIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO: 14) and the heavy chain of the antibody comprises the...

Claims

1. An anti-PD-1 antagonist antibody or its antigen-binding fragment and an anti-TIGIT antagonist antibody or its antigen-binding fragment for use as a medicinal product.

2. The anti-PD-1 antagonist antibody or its antigen-binding fragment and anti-TIGIT antagonist antibody or its antigen-binding fragment for use according to claim 1, wherein the drug is adapted to be administered in combination with at least one chemotherapeutic agent.

3. The anti-PD-1 antagonist antibody or its antigen-binding fragment and anti-TIGIT antagonist antibody or its antigen-binding fragment for use according to claim 1, wherein the drug is for use in the treatment or delay of cancer progression, reduction or inhibition of cancer recurrence, treatment or delay of the progression of an immune-related disease, or reduction or inhibition of the progression of an immune-related disease in an individual, wherein the immune-related disease is an unresolved acute infection, chronic infection, or tumor immunity.

4. The anti-PD-1 antagonist antibody or its antigen-binding fragment and anti-TIGIT antagonist antibody or its antigen-binding fragment for use according to claim 3, wherein the antibodies or the binding fragments thereof are adapted to be administered in combination with at least one chemotherapeutic agent.

5. The anti-PD-1 antagonist antibody or its antigen-binding fragment and anti-TIGIT antagonist antibody or its antigen-binding fragment for use according to any of claims 1-4, wherein the anti-TIGIT antagonist antibody or its antigen-binding fragment is a humanized antibody, a chimeric antibody, a bispecific antibody, a heteroconjugated antibody, or an immunotoxin.

6. The anti-PD-1 antagonist antibody or its antigen-binding fragment and anti-TIGIT antagonist antibody or its antigen-binding fragment for use according to any of claims 1-5, wherein the anti-PD-1 antagonist antibody or its antigen-binding fragment inhibits the binding of PD-1 to PD-L1, inhibits the binding of PD-1 to PD-L2, or inhibits the binding of PD-1 to both PD-L1 and PD-L2.

7. The anti-PD-1 antagonist antibody or its antigen-binding fragment and anti-TIGIT antagonist antibody or its antigen-binding fragment for use according to any of claims 1-6, wherein the anti-PD-1 antagonist antibody is MDX-1106, MK-3475 or CT-011.

8. The anti-PD-1 antagonist antibody or its antigen-binding fragment and the anti-TIGIT antagonist antibody or its antigen-binding fragment for use according to any one of claims 1-7, wherein the anti-TIGIT antagonist antibody inhibits or blocks the interaction of TIGIT with PVR, inhibits or blocks the interaction of TIGIT with PVRL2, inhibits or blocks the interaction of TIGIT with PVRL3, inhibits or blocks intracellular signaling mediated by TIGIT binding to PVR, inhibits or blocks intracellular signaling mediated by TIGIT binding to PVRL2, inhibits or blocks intracellular signaling mediated by TIGIT binding to PVRL3, or a combination thereof.

9. The anti-PD-1 antagonist antibody or its antigen-linking fragment and anti-TIGIT antagonist antibody or its antigen-linking fragment for use according to any of claims 1-8, wherein the anti-TIGIT antagonist antibody comprises six hypervariable regions having the amino acid sequences of: (1) KSSQSLYYSGVKENLLA (SEQ ID NO: 1), ASIRFT (SEQ ID NO: 2), QQGINNPLT (SEQ ID NO: 3), GFTFSSFTMH (SEQ ID NO: 4), FIRSGSGIVFYADAVRG (SEQ ID NO: 5), and RPLGHNTFDS (SEQ ID NO: 6); or (2) RSSQSLVNSYGNTFLS (SEQ ID NO:7), GISNRFS (SEQ ID NO:8), LQGTHQPPT (SEQ ID NO:9), GYSFTGHLMN (SEQ ID NO: 10), LIIPYNGGTSYNQKFKG (SEQ ID NO: 11), and GLRGFYAMDY (SEQ ID NO: 12).

10. The anti-PD-1 antagonist antibody or its antigen-linking fragment and anti-TIGIT antagonist antibody or its antigen-linking fragment for use according to any of claims 3-9, wherein the cancer is non-small cell lung cancer, small cell lung cancer, renal cell cancer, colorectal cancer, ovarian cancer, breast cancer, pancreatic cancer, gastric carcinoma, bladder cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer, thyroid cancer, sarcoma, prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphoma, myeloma, mycosis fungoides, Merkel cell cancer, or a hematologic disease.

11. The anti-PD-1 antagonist antibody or its antigen-binding fragment and anti-TIGIT antagonist antibody or its antigen-binding fragment for use according to any of claims 1-10, wherein the anti-TIGIT antagonist antibody or its antigen-binding fragment is adapted to be administered continuously or intermittently.

12. The anti-PD-1 antagonist antibody or its antigen-binding fragment and anti-TIGIT antagonist antibody or its antigen-binding fragment for use according to any of claims 1-10, wherein the anti-TIGIT antagonist antibody or its antigen-binding fragment is adapted to be administered before the anti-PD-1 antagonist antibody or its antigen-binding fragment, simultaneously with the anti-PD-1 antagonist antibody or its antigen-binding fragment, or after the anti-PD-1 antagonist antibody or its antigen-binding fragment.

13. A kit comprising an anti-PD-1 antagonist antibody or its antigen-binding fragment, an anti-TIGIT antagonist antibody or its antigen-binding fragment, and a packaging insert comprising instructions for using the anti-PD-1 antagonist antibody or its antigen-binding fragment and the anti-TIGIT antagonist antibody or its antigen-binding fragment to treat or delay the progression of cancer in an individual having cancer.

14. The kit of claim 13, wherein the anti-TIGIT antagonist antibody or its antigen-linking fragment is a humanized antibody, a chimeric antibody, a bispecific antibody, a heteroconjugated antibody, or an immunotoxin.

15. The kit of claim 13 or 14, wherein the anti-PD-1 antagonist antibody is MDX-1106, MK-3475 or hanonn / i zoz / e / yl CT-011.