新型免疫抑制受体TIGIT介导NK细胞免疫耗竭及其逆转机制研究

Checkpoint blockade targeting at inhibitory receptors is named as comes of new age of tumor immunotherapy, the key principle of which is to reverse the exhaustion of antitumor effector T cells induced in tumor microenvironment. Discovering new inhibitory receptor and then improving the antitumor function of corresponding effector cells become a pioneer research field, among which verifying whether there exists exhaustion of NK cells, another arm of antitumor effector cells aside T cells, and which inhibitory receptors on NK cells are checkpoints need study. TIGIT is a newly discovered inhibitory receptor expressed on NK cells, and our previous study has demonstrated that it exerts a key regulatory role to prevent acute immune injury in maintaining liver tolerance. Also, our preliminary results showed that NK cells become exhausted by expressing high TIGIT during tumor progress by using several murine tumor models. We are going to definitely verify if NK cells become exhausted, TIGIT is a checkpoint, anti-TIGIT efficiently reverses NK exhaustion and inhibits tumor growth, and importantly, the mechanistic role of TIGIT in negatively regulating NK-tumor interaction, by using TIGIT-KO mice, anti-TIGIT mAb, CD155 (a ligand of TIGIT)-KO tumor cells and a variety of immune cell-deficient mice (including T, B, NK cells).

抑制性受体作为Checkpoint阻断治疗被誉为肿瘤免疫治疗新时代来临，核心是逆转肿瘤微环境导致的抗癌效应T细胞（CTL）的免疫耗竭。发现新型抑制性受体及其对应的效应细胞成为前沿竞争焦点，其中验证与CTL同样重要的NK细胞是否存在Checkpoint及免疫耗竭显得十分重要与急迫。TIGIT分子是新近发现的抑制性受体，我们前期系列研究率先证实TIGIT分子是维持肝脏NK细胞免疫耐受的关键抑制性受体, 进而在多种肿瘤模型观察到NK细胞高表达TIGIT并与肿瘤发生发展密切相关。拟进一步采用TIGIT基因敲除鼠、自主获得的TIGIT单抗、TIGIT配体CD155基因敲除肿瘤细胞、T和B细胞缺陷鼠、NK细胞缺陷鼠等确证肿瘤发展中NK细胞是否存在耗竭、TIGIT是否为Checkpoint、抗TIGIT治疗可否高效逆转NK细胞耗竭并延缓肿瘤发展，及其TIGIT在NK细胞-肿瘤细胞互作中免疫负调机制。

基于免疫检查点的肿瘤免疫治疗目前吸引了大量的关注，很多研究表明阻断免疫检查点可以增强T细胞的效应功能，从而促进适应性免疫介导的抗肿瘤应答，PD-1/PD-L1和CTLA-4的阻断治疗在临床上也取得了惊人的疗效。TIGIT作为一个新兴的抑制性受体，会促进T细胞的耗竭，抑制T细胞介导的抗肿瘤免疫应答，从而促进肿瘤的发展。而在抗肿瘤免疫反应中，除了T细胞特异性识别肿瘤抗原之外，NK细胞也能发挥重要的抗肿瘤作用；为此采用不同肿瘤模型研究了在肿瘤发展过程中，TIGIT对NK细胞耗竭的影响，以及对NK细胞抗肿瘤免疫应答的影响，结果表明（1）TIGIT高表达于肿瘤浸润NK细胞上并促进NK细胞耗竭；（2）TIGIT缺失可逆转NK细胞耗竭并且促进肿瘤的清除；（3）TIGIT单独阻断可逆转NK细胞耗竭并且促进肿瘤的清除；（4） TIGIT介导的NK细胞耗竭不依赖于适应性免疫系统；（5）TIGIT阻断介导的NK细胞功能逆转不依赖于适应性免疫系统；（6）TIGIT/PD-L1阻断介导的增强的适应性免疫应答依赖于NK细胞；（7）TIGIT单独阻断能够激发潜在的抗肿瘤记忆应答。