Department of Medicine and Division of Hematology/Oncology and.
Department of Biostatistics, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.
JCI Insight. 2018 Jul 26;3(14). doi: 10.1172/jci.insight.121157.
CD4+ Tregs impede T cell responses to tumors. They express multiple inhibitory receptors that support their suppressive functions, including T cell Ig and ITIM domain (TIGIT). In melanoma patients, we show that Tregs exhibit increased TIGIT expression and decreased expression of its competing costimulatory receptor CD226 as compared with CD4+ effector T cells, resulting in an increased TIGIT/CD226 ratio. Tregs failed to upregulate CD226 upon T cell activation. TIGIT+ Tregs are highly suppressive, stable, and enriched in tumors. TIGIT and CD226 oppose each other to augment or disrupt, respectively, Treg suppression and stability. A high TIGIT/CD226 ratio in Tregs correlates with increased Treg frequencies in tumors and poor clinical outcome upon immune checkpoint blockade. Altogether, our findings show that a high TIGIT/CD226 ratio in Tregs regulates their suppressive function and stability in melanoma. They provide the rationale for novel immunotherapies to activate CD226 in Tregs together with TIGIT blockade to counteract Treg suppression in cancer patients.
CD4+Tregs 抑制 T 细胞对肿瘤的反应。它们表达多种抑制性受体，支持其抑制功能，包括 T 细胞免疫球蛋白和 ITIM 结构域（TIGIT）。在黑色素瘤患者中，我们发现与 CD4+效应 T 细胞相比，Tregs 表现出更高的 TIGIT 表达和更低的竞争共刺激受体 CD226 表达，导致 TIGIT/CD226 比值增加。Tregs 在 T 细胞激活时未能上调 CD226。TIGIT+Tregs 具有高度抑制性、稳定性，并在肿瘤中富集。TIGIT 和 CD226 相互拮抗，分别增强或破坏 Treg 的抑制和稳定性。Tregs 中的高 TIGIT/CD226 比值与肿瘤中 Treg 频率的增加以及免疫检查点阻断后的不良临床结果相关。总之，我们的研究结果表明，Tregs 中的高 TIGIT/CD226 比值调节其在黑色素瘤中的抑制功能和稳定性。它们为新型免疫疗法提供了依据，即在阻断 TIGIT 的同时激活 Tregs 中的 CD226，以抵消癌症患者中 Treg 的抑制作用。
