Dysfunctional antigen-specific cd8+ t cells in the tumor microenvironment

Abstract

Provided herein are compositions and methods for detecting and/or targeting dysfunctional tumor antigen-specific CD8+ T cells in the tumor microenvironment for diagnostic, therapeutic and/or research applications. In particular, dysfunctional tumor antigen-specific CD8+ T cells are detected and/or targeted via their expression of cell surface receptors described herein, such as 4-1BB, LAG-3, or additional markers that correlate with 4-1BB and LAG-3 expression, such as markers differentially expressed on the surface of the T cells.

1 . A method of treating a subject with cancer comprising administering an agent that specifically targets dysfunctional tumor antigen-specific CD8 +  T cells. 
     
     
         2 . The method of  claim 1 , wherein the subject suffers from a solid tumor cancer. 
     
     
         3 . The method of  claim 2 , wherein the tumor allows T cell infiltration, but is resistant to immunotherapies. 
     
     
         4 . The method of  claim 2 , wherein the tumor environment comprises dysfunctional tumor antigen-specific CD8 +  T cells. 
     
     
         5 . The method of  claim 1 , comprising contacting the dysfunctional tumor antigen-specific CD8 +  T cells with an anti-4-1BB and/or anti-LAG3 agent. 
     
     
         6 . The method of  claim 5 , wherein the anti-4-1BB and/or anti-LAG3 agent is an antibody, antibody fragment, or antibody mimetic molecule. 
     
     
         7 . The method of  claim 1 , further comprising co-administration of an additional therapeutic agent. 
     
     
         8 . The method of  claim 7 , wherein the additional therapeutic agent is a chemotherapeutic or an immunotherapeutic agent. 
     
     
         9 . The method of  claim 8 , wherein the additional therapeutic agent is an immunotherapeutic agent selected from the list consisting of cell-based therapies, monoclonal antibody (mAb) therapy, cytokine therapy, and adjuvant treatment. 
     
     
         10 . The method of  claim 9 , wherein the immunotherapeutic agent is a mAb therapy selected from the list consisting of anti-CTLA-4 monoclonal antibodies and/or anti-PD-L1 monoclonal antibodies. 
     
     
         11 . The method of  claim 9 , wherein the immunotherapeutic agent is a cell-based therapy selected from the list consisting of dendritic-cell therapy and T-cell therapy. 
     
     
         12 . The method of  claim 7 , wherein the additional therapeutic agent targets one of the receptors listed in Table 2. 
     
     
         13 . The method of  claim 7 , wherein the additional therapeutic agent targets PD-1, TIM-3, OX-40ICOS, TIGIT, CD244, TNFRSF18, Nrn1, Nrp1, KLRG1, GM156, GPNMB, GPR65, TMEM205, and TMEM126A, Nrn1, CRTAM and/or Sema7a. 
     
     
         14 . The method of  claim 1 , comprising contacting the dysfunctional tumor antigen-specific CD8 +  T cells with a therapeutic agent that targets one of the receptors listed in Table 2. 
     
     
         15 . The method of  claim 14 , wherein the therapeutic agent targets PD-1, TIM-3, OX-40ICOS, TIGIT, CD244, TNFRSF18, Nrn1, Nrp1, KLRG1, GM156, GPNMB, GPR65, TMEM205, and TMEM126A, Nrn1, CRTAM and/or Sema7a. 
     
     
         16 . The method of  claim 15 , wherein the therapeutic agent is an anti-Nrn1 antibody, antibody fragment, or antibody mimetic molecule. 
     
     
         17 . The method of  claim 15 , wherein the therapeutic agent is an anti-Sema7a antibody, antibody fragment, or antibody mimetic molecule. 
     
     
         18 . The method of  claim 15 , wherein the therapeutic agent is an anti-CRTAM antibody, antibody fragment, or antibody mimetic molecule. 
     
     
         19 . A composition comprising: (a) one or more of an anti-4-1BB agent, an anti-LAG-3 agent, an anti-Nrn1 agent, an anti-Sema7a agent, and an anti-CRTAM agent; and (b) an immunotherapeutic agent, said composition formulated for therapeutic delivery to a subject. 
     
     
         20 . The composition of  claim 19 , wherein the anti-4-1BB agent, anti-LAG-3 agent, anti-Nrn1 agent, anti-Sema7a agent, and/or anti-CRTAM agent is an antibody, antibody fragment, or antibody mimetic molecule. 
     
     
         21 . A method comprising: (a) testing CD8 +  T cells from a cell population to determine whether they co-express LAG-3 and 4-1BB; and (b) administering an anti-Nrn1 agent, an anti-Sema7a agent, and an anti-CRTAM agent. 
     
     
         22 . The method of  claim 21 , wherein the anti-Nrn1 agent, anti-Sema7a agent, and/or anti-CRTAM agent is an antibody, antibody fragment, or antibody mimetic molecule. 
     
     
         23 . The method of  claim 21 , wherein said testing is performed in vitro. 
     
     
         24 . A method of identifying dysfunctional T cells by testing said cells for co-expression of 4-1BB and LAG-3.