免疫抑制受体CD112R介导NK细胞耗竭及其逆转

基于T细胞的检查点(Checkpoint)免疫治疗取得了举世瞩目的成就，拉开了寻找新抑制性受体作为阻断靶点的研究序幕。过去10年我们发现NK细胞与T细胞一样存在免疫耗竭，发现了几个国际认可的NK细胞抑制性受体为潜在的检查点。CD112R是近年发现的免疫抑制性受体，我们前期证实多种小鼠肿瘤中NK细胞高表达CD112R并与其免疫耗竭相关。拟进一步采用自主构建的CD112R基因敲除鼠、自主获得的CD112R单抗、T或B或NK细胞缺陷鼠等确证肿瘤发展中NK细胞的免疫耗竭分子谱系、CD112R是否为免疫检查点、抗CD112R治疗可否逆转NK细胞耗竭并阻滞肿瘤发展，CD112R在NK细胞-肿瘤细胞（或其它组织细胞）互作的免疫负调机制，以及与NK细胞耗竭的关系。该研究可能确证CD112R为潜在检查点并验证NK细胞的耗竭机制及其肿瘤免疫治疗价值。

T cell-based checkpoint immunotherapy creates the history of tumor treatment, and looking for new targets, particularly inhibitory receptors, for checkpoint blockade is at beginning. In past 10 years, we observed that NK cells also become exhausted during tumor progress, and found several NK cell inhibitory receptors being working as checkpoints, among which CD112R, a recently recognized inhibitory receptor, highly expressed on NK cells and induced their functional exhaustion in tumor microenvironment in our previous studies. We are going to definitely verify if NK cells become exhausted in CD112R-dependent manner and if CD112Rworks as a checkpoint, and if anti-CD112Rantibody efficiently reverses NK exhaustion and inhibits tumor growth, and importantly, what is the mechanistic role of CD112R in negatively regulating NK-tumor interaction (and other tissue cells in tumor microenvironment), by using our CD112R-KO mice, our anti-CD112R mAb and a variety of immune cell-deficient mice (including T, B, NK cells).