Chauvin Joe-Marc, Pagliano Ornella, Fourcade Julien, Sun Zhaojun, Wang Hong, Sander Cindy, Kirkwood John M, Chen Tseng-hui Timothy, Maurer Mark, Korman Alan J, Zarour Hassane M
J Clin Invest. 2015 May;125(5):2046-58. doi: 10.1172/JCI80445. Epub 2015 Apr 13.
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.
T细胞免疫球蛋白和免疫酪氨酸抑制基序结构域（TIGIT）是一种由活化的T细胞、调节性T细胞（Tregs）和自然杀伤细胞（NK细胞）表达的抑制性受体。在此，我们确定TIGIT在黑色素瘤患者的肿瘤抗原特异性（TA特异性）CD8⁺T细胞和CD8⁺肿瘤浸润淋巴细胞（TILs）上表达上调，并且这些表达TIGIT的CD8⁺T细胞通常共表达抑制性受体程序性死亡蛋白1（PD-1）。此外，来自患者的CD8⁺TILs共刺激分子CD226表达下调，CD226与TIGIT竞争相同配体，这支持转移性黑色素瘤中TIGIT/CD226失衡。TIGIT标志着早期T细胞活化，并且在PD-1阻断后以及在功能失调的PD-1⁺T细胞免疫球蛋白和粘蛋白结构域3（TIM-3）⁺TA特异性CD8⁺T细胞中被T细胞进一步上调。体外实验中，PD-1⁺TIGIT⁺、PD-1⁻TIGIT⁺和PD-1⁺TIGIT⁻CD8⁺TILs具有相似的功能能力，这表明单独的TIGIT或与PD-1一起，并不表明T细胞功能障碍。然而，在存在表达TIGIT配体的细胞的情况下，TIGIT和PD-1阻断可累加增加TA特异性CD8⁺T细胞和CD8⁺TILs的增殖、细胞因子产生和脱颗粒。总体而言，我们的结果表明，TIGIT和PD-1调节黑色素瘤患者中TA特异性CD8⁺T细胞和CD8⁺TILs的扩增和功能，并表明应进一步探索双重TIGIT和PD-1阻断，以在晚期黑色素瘤患者中引发有效的抗肿瘤CD8⁺T细胞反应。
