Immune checkpoint inhibitors show great promise as therapy for advanced melanoma, heightening the need to determine the most effective use of these agents. Here, we report that programmed death-1^high (PD-1^high) tumor antigen (TA)–specific CD8⁺ T cells present at periphery and at tumor sites in patients with advanced melanoma upregulate IL10 receptor (IL10R) expression. Multiple subsets of peripheral blood mononucleocytes from melanoma patients produce IL10, which acts directly on IL10R⁺ TA-specific CD8⁺ T cells to limit their proliferation and survival. PD-1 blockade augments expression of IL10R by TA-specific CD8⁺ T cells, thereby increasing their sensitivity to the immunosuppressive effects of endogenous IL10. Conversely, IL10 blockade strengthened the effects of PD-1 blockade in expanding TA-specific CD8⁺ T cells and reinforcing their function. Collectively, our findings offer a rationale to block both IL10 and PD-1 to strengthen the counteraction of T-cell immunosuppression and to enhance the activity of TA-specific CD8⁺ T cell in advanced melanoma patients. Cancer Res; 75(8); 1635–44. ©2015 AACR.