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.
The proposed study aims at understanding the failure of T cell immune responses to promote melanoma regression. This research project is therefore critical for the design of novel therapeutic interventions aimed at overcoming tumor-induced immune escape and stimulating potent anti-tumor responses in melanoma patients.
|Zarour, Hassane M (2016) Reversing T-cell Dysfunction and Exhaustion in Cancer. Clin Cancer Res 22:1856-64|
|Whiteside, Theresa L; Demaria, Sandra; Rodriguez-Ruiz, Maria E et al. (2016) Emerging Opportunities and Challenges in Cancer Immunotherapy. Clin Cancer Res 22:1845-55|
|Chauvin, Joe-Marc; Pagliano, Ornella; Fourcade, Julien et al. (2015) TIGIT and PD-1 impair tumor antigen-specific CD8âº T cells in melanoma patients. J Clin Invest 125:2046-58|
|Sun, Zhaojun; Fourcade, Julien; Pagliano, Ornella et al. (2015) IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells. Cancer Res 75:1635-44|
|Fourcade, Julien; Sun, Zhaojun; Pagliano, Ornella et al. (2014) PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8âº T cells induced by melanoma vaccines. Cancer Res 74:1045-55|
|Fourcade, Julien; Zarour, Hassane M (2013) Strategies to reverse melanoma-induced T-cell dysfunction. Clin Dermatol 31:251-6|
|Kirkwood, John M; Butterfield, Lisa H; Tarhini, Ahmad A et al. (2012) Immunotherapy of cancer in 2012. CA Cancer J Clin 62:309-35|
|Fourcade, Julien; Sun, Zhaojun; Pagliano, Ornella et al. (2012) CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res 72:887-96|
|Kudela, Pavol; Sun, Zhaojun; Fourcade, Julien et al. (2011) Epitope hierarchy of spontaneous CD4+ T cell responses to LAGE-1. J Immunol 186:312-22|