Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients.
Fourcade, Julien 1; Sun, Zhaojun 1; Benallaoua, Mourad 1; Guillaume, Philippe 3; Luescher, Immanuel F. 3; Sander, Cindy 1; Kirkwood, John M. 1; Kuchroo, Vijay 4; Zarour, Hassane M. 1,2
[Article] Journal of Experimental Medicine. 207(10):2175-2186, September 27, 2010.

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The paradoxical coexistence of spontaneous tumor antigen-specific immune responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction. In patients with advanced melanoma, we have previously shown that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1-specific CD8 T cells that up-regulate PD-1 expression. We also observed that PD-1 regulates NY-ESO-1-specific CD8 T cell expansion upon chronic antigen stimulation. In the present study, we show that a fraction of PD-1 NY-ESO-1-specific CD8 T cells in patients with advanced melanoma up-regulates Tim-3 expression and that Tim-3 PD-1 NY-ESO-1-specific CD8 T cells are more dysfunctional than Tim-3-PD-1 and Tim-3-PD-1- NY-ESO-1-specific CD8 T cells, producing less IFN-[gamma], TNF, and IL-2. Tim-3-Tim-3L blockade enhanced cytokine production by NY-ESO-1-specific CD8 T cells upon short ex vivo stimulation with cognate peptide, thus enhancing their functional capacity. In addition, Tim-3-Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1-specific CD8 T cells upon prolonged antigen stimulation and acted in synergy with PD-1-PD-L1 blockade. Collectively, our findings support the use of Tim-3-Tim-3L blockade together with PD-1-PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.

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