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TIGIT and PD-1 impair tumor antigen–specific CD8+ T cells in melanoma patients
Joe-Marc Chauvin, … , Alan J. Korman, Hassane M. Zarour
Joe-Marc Chauvin, … , Alan J. Korman, Hassane M. Zarour
Published April 13, 2015
Citation Information: J Clin Invest. 2015;125(5):2046-2058. https://doi.org/10.1172/JCI80445.
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Research Article Oncology

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

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Abstract

T cell Ig and ITIM domain (TIGIT) is an inhibitory receptor expressed by activated T cells, Tregs, and NK 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 CD8+ 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.

Authors

Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Hong Wang, Cindy Sander, John M. Kirkwood, Tseng-hui Timothy Chen, Mark Maurer, Alan J. Korman, Hassane M. Zarour

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Figure 1

TIGIT is upregulated and coexpressed with PD-1 on NY-ESO-1–specific CD8+ T cells.

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TIGIT is upregulated and coexpressed with PD-1 on NY-ESO-1–specific CD8+...
(A) Representative dot plots for 1 melanoma patient showing ex vivo TIGIT expression on A2/NY-ESO-1 157-165, A2/Flu-M 58-66, and A2/CMV 495-503 tet+ CD8+ T cells. CD8+ T cells stained with A2/HIV pol 476-484 tetramers or PE-labeled IgG control mAbs were used to establish the threshold for identifying tet+ and TIGIT+ cells, respectively. (B) Pooled data showing the percentage and MFI of TIGIT expression on NY-ESO-1–, Flu-, and CMV-specific CD8+ T cells as well as on total effector (CD45RA+CCR7–) and effector memory (CD45RO+CCR7–) CD8+ T cells from melanoma patients (n = 8). P values were obtained by repeated-measures ANOVA, followed by Tukey’s multiple comparisons test. (C) Dot plots for 1 representative melanoma patient showing ex vivo TIGIT and PD-1 expression on A2/NY-ESO-1 157-165, A2/Flu-M 58-66, and A2/CMV 495-503 tet+ CD8+ T cells as well as on total tet– CD8+ T cells. (D) Pooled data showing the distribution of NY-ESO-1–, Flu-, and CMV-specific CD8+ T cells, as well as of total effector and effector memory CD8+ T cells according to TIGIT and PD-1 expression in cells from melanoma patients (n = 8). P values were obtained by Friedman’s test, followed by Dunn’s multiple comparisons test. Horizontal bars depict the mean percentage or MFI. *P < 0.05; **P < 0.01; ***P < 0.001. Data shown are representative of 3 independent experiments.
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