Abstract 3657: Upregulation of PD-1 and Tim-3 expression on tumor antigen-specific CD4+ T cells is associated with reversible T cell dysfunction in patients with advanced melanoma

Abstract

Abstract The paradoxical coexistence of spontaneous tumor antigen-specific immune T cell responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction and exhaustion. We have previously observed in patients with advanced melanoma that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1-specific CD8+ T cells that upregulate PD-1 expression and that a fraction of PD-1+ NY-ESO-1-specific CD8+ T cells upregulates Tim-3 expression. We have found that Tim-3+PD-1+ NY-ESO-1-specific CD8+ T cells represent highly dysfunctional T cells in terms of cytokine production and proliferation. Importantly, Tim-3/Tim-3L blockade together with PD-1/PD-L1 blockade enhanced cytokine production and proliferation of NY-ESO-1-specific CD8+ T cells upon prolonged antigen stimulation. Whether the upregulation of PD-1 and Tim-3 is associated with tumor antigen-specific CD4+ T cell dysfunction/exhaustion in patients with advanced melanoma remains unknown. Here, our findings show that in contrast to EBV-specific, CMV-specific and total CD4+ T cells, PD-1 and Tim-3 expression is upregulated by NY-ESO-1-specific CD4+ T cells isolated from peripheral blood lymphocytes of patients with advanced melanoma. Interestingly, PD-1/PD-L1 blockade synergized with Tim-3/Tim-3L pathway blockade to restore the numbers of cytokine-producing and proliferating NY-ESO-1-specific CD4+ T cells. Collectively, our findings support the use of Tim-3/Tim-3L blockade in association with PD-1/PD-L1 blockade to reverse tumor-induced CD8+ and CD4+ T cell exhaustion/dysfunction in patients with advanced melanoma. Our findings have significant implication in terms of novel immunotherapeutic strategies aiming at promoting T cell-mediated tumor regression in patients with advanced cancers. This work was supported by NIH/NCI Grants CA90360 and CA112198 (HMZ) and Cancer Research Institute grant (HMZ). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3657. doi:10.1158/1538-7445.AM2011-3657