靶向TIGIT配体CD155以逆转NK细胞免疫耗竭及其机制

抑制性受体(Checkpoint)介导的免疫耗竭是NK细胞抗肿瘤潜能受限的关键机制。我们最近报道了抑制性受体TIGIT可负调NK细胞功能，靶向TIGIT可逆转NK细胞免疫耗竭并阻滞肿瘤生长(Nat Immunol 2018)。我们在肿瘤病人队列还观察到TIGIT配体CD155在肿瘤的表达与NK细胞功能耗竭及其病人生存率均呈负相关。拟进一步在荷瘤小鼠模型①验证共享CD155配体的受体家族分子的动态表达谱及其与NK细胞耗竭的时序特征；②确证靶向CD155的抗体或CD155基因敲除能否阻滞或逆转NK细胞耗竭并抑制肿瘤发展；③深入探讨CD155在NK细胞-肿瘤细胞互作的免疫负调机制及其与NK细胞耗竭的确切关系，佐证CD155-TIGIT互作既可负调NK细胞功能又可正调肿瘤细胞自身抑制性配体表达的“双负调信号”的假设。本研究将揭示CD155介导NK细胞免疫耗竭机制及其在肿瘤免疫治疗中的价值。

Immune exhaustion mediated by checkpoint receptors is the major mechanism for the diminished NK cell anti-tumor functions in tumors. We recently reported that checkpoint receptor TIGIT negatively regulates NK cell functions, and that targeting TIGIT reverses NK cell exhaustion and suppresses tumor growth (Nat Immunol 2018). We further found that CD155, ligand for TIGIT, negatively correlates with NK cell signatures and survival of tumor patients. Based on these, we plan to do further research on mouse tumor models: ① to study the kinetics of CD155 receptors expression in parallel with NK cell exhaustion; ② to reveal whether CD155 blockade or deficiency could inhibit or reverse NK cell exhaustion and suppress tumor development; ③ to investigate the regulatory role of CD155 in NK-tumor cell interactions, as well as its effects on NK cell exhaustion, so as to support the “dual negative regulation”hypothesis that CD155-TIGIT interactions on one hand negatively regulate NK cell functions, and on the other hand positively regulate the expression of the inhibitory ligand CD155 itself. The current study might discover novel mechanisms underlying CD155-mediated NK cell exhaustion, as well as its value in tumor immunotherapy.