TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients

T cell Ig and ITIM domain (TIGIT) is an inhibitory receptor expressed by activated T cells, Tregs, and NI( cells. Here, we determined that TIGIT is upregulated on tumor antigen specific (TA-specific) CD8(+) T cells and CD8+ tumor-infiltrating lymphocytes (TILs) from patients with melanoma, and these TIGIT-expressing CD8(+) T cells often coexpress the inhibitory receptor PD-1. Moreover, CD8(+)TILs from patients exhibited downregulation of the costimulatory molecule CD226, which competes with TIGIT for the same ligand, supporting a TIGIT/CD226 imbalance in metastatic melanoma. TIGIT marked early T cell activation and was further upregulated by T cells upon PD-1 blockade and in dysfunctional PD-1(+)TIM-3(+) TA-specific CD8(+) T cells. PD-1(+)TIGIT(+), PD-1(-)TIGIT(+), and PD-1(+)TIGIT(-)CD8(+) TILs had similar functional capacities ex vivo, suggesting that TIGIT alone, or together with PD-1, is not indicative of T cell dysfunction. However, in the presence of TIGIT ligand expressing cells, TIGIT and PD-1 blockade additively increased proliferation, cytokine production, and degranulation of both TA-specific CD8(+) T cells and COW TILs. Collectively, our results show that TIGIT and PD-1 regulate the expansion and function of TA-specific CD8(+) T cells and CD8(+) TILs in melanoma patients and suggest that dual TIGIT and PD-1 blockade should be further explored to elicit potent antitumor CD8(+) T cell responses in patients with advanced melanoma.