Journal Article

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

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

2015

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - pharmacology / Antigen-Presenting Cells - immunology / Antigen-Presenting Cells - metabolism / Antigens, Differentiation, T-Lymphocyte - biosynthesis / Antigens, Differentiation, T-Lymphocyte - genetics / Antigens, Neoplasm - immunology / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell Line, Tumor / Cytokines - biosynthesis / Gene Expression Regulation, Neoplastic / Humans / Immunologic Memory / Immunophenotyping / Interleukin-2 Receptor beta Subunit - biosynthesis / Interleukin-2 Receptor beta Subunit - genetics / Lymphocyte Activation / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - metabolism / Melanoma - immunology / Melanoma - pathology / Neoplasm Proteins - antagonists & inhibitors / Neoplasm Proteins - biosynthesis / Neoplasm Proteins - genetics / Neoplasm Proteins - physiology / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - biosynthesis / Programmed Cell Death 1 Receptor - genetics / Programmed Cell Death 1 Receptor - physiology / Receptors, Immunologic - antagonists & inhibitors / Receptors, Immunologic - biosynthesis / Receptors, Immunologic - genetics / Receptors, Immunologic - physiology / Receptors, Virus - biosynthesis / Receptors, Virus - genetics / T-Cell Antigen Receptor Specificity / Up-Regulation