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

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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 5 Pg. 2046-58 (May 2015) ISSN: 1558-8238 [Electronic] United States
• PMID: 25866972 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antigens, Differentiation, T-Lymphocyte
• Antigens, Neoplasm
• CD226 antigen
• Cytokines
• IL2RB protein, human
• Interleukin-2 Receptor beta Subunit
• Neoplasm Proteins
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Receptors, Immunologic
• Receptors, Virus
• TIGIT protein, human
• poliovirus receptor

Topics

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