Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Rev Immunol. 2020 Mar;20(3):173-185. doi: 10.1038/s41577-019-0224-6. Epub 2019 Nov 1.
T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a member of the TIM family, was originally identified as a receptor expressed on interferon-γ-producing CD4 and CD8 T cells. Initial data indicated that TIM3 functioned as a 'co-inhibitory' or 'checkpoint' receptor, but due to the lack of a definable inhibitory signalling motif, it was also suggested that TIM3 might act as a co-stimulatory receptor. Recent studies have shown that TIM3 is part of a module that contains multiple co-inhibitory receptors (checkpoint receptors), which are co-expressed and co-regulated on dysfunctional or 'exhausted' T cells in chronic viral infections and cancer. Furthermore, co-blockade of TIM3 and programmed cell death 1 (PD1) can result in tumour regression in preclinical models and can improve anticancer T cell responses in patients with advanced cancers. Here, we highlight the developments in understanding TIM3 biology, including novel ligand identification and the discovery of loss-of-function mutations associated with human disease. In addition, we summarize emerging data from human clinical trials showing that TIM3 indeed acts as a 'checkpoint' receptor and that inhibition of TIM3 enhances the antitumour effect of PD1 blockade.
T 细胞免疫球蛋白和黏蛋白结构域蛋白 3（TIM3）是 TIM 家族的一员，最初被鉴定为干扰素-γ 产生的 CD4 和 CD8 T 细胞上表达的受体。最初的数据表明 TIM3 作为“共抑制”或“检查点”受体发挥作用，但由于缺乏可定义的抑制信号基序，也有人提出 TIM3 可能作为共刺激受体发挥作用。最近的研究表明，TIM3 是包含多个共抑制受体（检查点受体）的模块的一部分，这些受体在慢性病毒感染和癌症中的功能失调或“耗竭”T 细胞上共表达和共调节。此外，TIM3 和程序性细胞死亡 1（PD1）的共阻断可导致临床前模型中的肿瘤消退，并可改善晚期癌症患者的抗肿瘤 T 细胞反应。在这里，我们强调了对 TIM3 生物学的理解的发展，包括新型配体的鉴定和与人类疾病相关的功能丧失突变的发现。此外，我们总结了来自人类临床试验的新数据，表明 TIM3 确实作为“检查点”受体发挥作用，并且抑制 TIM3 增强了 PD1 阻断的抗肿瘤作用。
