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Reversing melanoma-induced T cell dysfunction

Hassane M Zarour

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National Cancer Institute (NIH)
There is ample evidence that patients with melanoma can develop immune responses directed against antigens expressed by their own tumor. However, very high frequencies of spontaneous or vaccine-induced tumor antigen (TA)-specific cytotoxic T cells (CTLs) have failed to induce melanoma rejection. Understanding the failure of spontaneous TA-specific T cell responses to promote regression of melanoma is therefore critical for the design of novel therapeutic interventions aimed at overcoming tumor-induced immune escape. Among the numerous mechanisms of tumor-induced immunosuppression that contribute to the resistance of tumors to cytotoxic T cells, a number of experimental studies in animals and in humans have suggested the role of co- inhibitory pathways like programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interactions in inhibiting the effector functions of TA-specific CD8+ T cells. Spontaneous TA-specific CD8+ T cells in peripheral blood lymphocytes (PBLs) or tumor-infiltrating lymphocytes (TILs) of patients with advanced melanoma appear to upregulate PD-1 expression. PD-1 is a regulator of TA-specific CD8+ T cell expansion in the context of chronic antigen stimulation. However, PD-1 upregulation alone on spontaneous TA-specific CD8+ T cells is not consistently and directly associated with T cell dysfunction on a cell-per-cell basis. This critical observation raises the hypothesis that the co-expression of multiple co-inhibitory receptors including PD-1 may be expressed by highly dysfunctional/exhausted T cells, as previously observed in virus-specific CD8+ T cells in mice with chronic viral infections. Here, we propose to address this question and investigate whether other co-inhibitory molecular pathways are involved in TA-specific T cell dysfunction in patients with advanced melanoma. We will also investigate whether blockade of these pathways may act synergistically with PD-1/PD-L1 pathway blockade to reverse melanoma-induced T cell dysfunction of TA-specific CD8+ and CD4+ T cells in PBLs and TILs of patients with advanced melanoma. Collectively, the findings derived from the outlined studies will support the use of combinatorial co-inhibitory pathway blockades in immunotherapeutic interventions to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.

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