Upregulation of Tim-3 and PD-1 Expression is Associated with Tumor Antigen-Specific CD8\(^+\) T Cell Dysfunction in Melanoma Patients

Fourcade, JulienSun, ZhaojunBenallaoua, MouradGuillaume, PhilippeLuescher, Immanuel F.Sander, CindyKirkwood, John M.Kuchroo, VijayZarour, Hassane M.2011-12-062010Fourcade, Julien, Zhaojun Sun, Mourad Benallaoua, Philippe Guillaume, Immanuel F. Luescher, Cindy Sander, John M. Kirkwood, Vijay Kuchroo, and Hassane M. Zarour. 2010. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8\(^+\) T cell dysfunction in melanoma patients. The Journal of Experimental Medicine 207(10): 2175-2186.0022-1007http://nrs.harvard.edu/urn-3:HUL.InstRepos:5361375The 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-γ, TNF, and IL-2. Tim-3–Tim-3L block- ade 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.en-USUpregulation of Tim-3 and PD-1 Expression is Associated with Tumor Antigen-Specific CD8\(^+\) T Cell Dysfunction in Melanoma PatientsJournal Article2011-12-0610.1084/jem.20100637