Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity
Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity
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阻断检查点受体 TIGIT 可防止 NK 细胞耗竭并引发有效的抗肿瘤免疫
DOI：
10.1038/s41590-018-0132-0
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发表时间：
2018-07-01
影响因子：
30.5
通讯作者：
Tian, Zhigang
中科院分区：
文献类型：
--
作者：
Zhang, Qing;Bi, Jiacheng;Tian, Zhigang
检查点阻断增强效应T细胞功能，并在一部分广谱癌症患者中引起长期缓解。TIGIT是一种被认为参与介导肿瘤中T细胞耗竭的检查点受体;然而，TIGIT与自然杀伤（NK）细胞功能障碍的相关性仍然知之甚少。在这里，我们发现TIGIT，而不是其他检查点分子CTLA-4和PD-1，与荷瘤小鼠和结肠癌患者的NK细胞耗竭相关。在几种荷瘤小鼠模型中，阻断TIGIT防止NK细胞耗竭并促进NK细胞依赖性肿瘤免疫。此外，TIGIT的阻断以NK细胞依赖性方式导致有效的肿瘤特异性T细胞免疫，用针对PD-1配体PD-L1的抗体增强的治疗和肿瘤再攻击模型中的持续记忆免疫。这项工作表明，TIGIT构成了NK细胞中以前未被重视的检查点，并且单独靶向TIGIT或与其他检查点受体组合靶向TIGIT是一种有前途的抗癌治疗策略。
Checkpoint blockade enhances effector T cell function and has elicited long-term remission in a subset of patients with a broad spectrum of cancers. TIGIT is a checkpoint receptor thought to be involved in mediating T cell exhaustion in tumors; however, the relevance of TIGIT to the dysfunction of natural killer (NK) cells remains poorly understood. Here we found that TIGIT, but not the other checkpoint molecules CTLA-4 and PD-1, was associated with NK cell exhaustion in tumor-bearing mice and patients with colon cancer. Blockade of TIGIT prevented NK cell exhaustion and promoted NK cell–dependent tumor immunity in several tumor-bearing mouse models. Furthermore, blockade of TIGIT resulted in potent tumor-specific T cell immunity in an NK cell–dependent manner, enhanced therapy with antibody to the PD-1 ligand PD-L1 and sustained memory immunity in tumor re-challenge models. This work demonstrates that TIGIT constitutes a previously unappreciated checkpoint in NK cells and that targeting TIGIT alone or in combination with other checkpoint receptors is a promising anti-cancer therapeutic strategy.