title: 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
authors: JM
authors: Chauvin
authors: Ornella
authors: O
authors: Pagliano
authors: Julien
authors: J
authors: Fourcade
authors: Zhaojun
authors: Z
authors: Sun
authors: Hong
authors: H
authors: Wang
authors: Cindy
authors: C
authors: Sander
authors: John M
authors: JM
authors: Kirkwood
authors: Tseng-hui Timothy
authors: TH
authors: Chen
authors: Mark
authors: M
authors: Maurer
authors: Alan J
authors: AJ
authors: Korman
authors: Hassane M
authors: HM
authors: Zarour
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D053646:Interleukin-2 Receptor beta Subunit / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011991:Receptors, Virus / Q000096:biosynthesis / Q000235:genetics; D037182:T-Cell Antigen Receptor Specificity; D015854:Up-Regulation; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D000098862:T Lineage-Specific Activation Antigen 1; D016207:Cytokines; C508020:IL2RB protein, human; D053646:Interleukin-2 Receptor beta Subunit; D009363:Neoplasm Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C534712:TIGIT protein, human; C066100:poliovirus receptor