肿瘤微环境中Tim-3调控CD8+ T细胞功能和耗竭的作用机制

Malignant tumors have posed a serious threat to human health. CD8+ cytotoxic T lymphocytes (CTL) play an important role in the elimination of tumors. However, CD8+ T cells often become exhausted in the tumor microenvironment, leading to the failure of cancer elimination. Previous study in both animal experiments and cancer patients have shown that inhibitory receptor Tim-3 is associated with CD8+ T cell exhaustion, and blockade of Tim-3 signals could restore function of exhausted CD8+ T cells. Tim-3 has received increasing attention as a promising target in tumor immunotherapy. However, it remains unclear what role Tim-3 signals play in initiating and/or establishing the program of T cell exhaustion in the tumor microenvironment, and how Tim-3 signals regulate the anti-tumor function of CD8+ T cells in detail. Moreover, very little is known about the downstream signaling pathways of Tim-3. In this study, we will use Tim-3 deficient mice and tumor mouse model to investigate the role and mechanism of Tim-3 in regulating CD8+ T cell function and exhaustion, and aim to elucidate the downstream signaling pathways and molecular mechanism of Tim-3. Our study will further deepen the knowledge of tumor immune escape, and provide novel strategies and new therapeutic target for clinical tumor immunotherapy.

恶性肿瘤严重困扰人类健康。CD8+ 细胞毒性T淋巴细胞（CTL）在清除肿瘤中起到了重要作用，而在肿瘤微环境中CD8+ T细胞发生功能耗竭，导致肿瘤不能被清除。已有的动物模型和临床病人的研究表明，耗竭CD8+ T细胞上表达抑制性受体Tim-3，并且阻断Tim-3可以恢复耗竭CD8+ T细胞的功能。Tim-3作为肿瘤免疫治疗的热点靶分子受到极大关注。然而，目前仍不清楚在肿瘤微环境中Tim-3是否直接诱导CD8+ T细胞发生功能耗竭以及如何调控CD8+ T细胞抗肿瘤功能，而且对于Tim-3下游信号通路所知甚少。本课题使用基因敲除小鼠和肿瘤模型，并结合影像学方法(活细胞工作站和共聚焦显微镜)，重点研究Tim-3在CD8+ T细胞发生耗竭以及抗肿瘤反应中的作用，并深入探讨其下游信号转导机制。本研究将加深对肿瘤免疫逃逸的了解，为临床肿瘤免疫治疗提供新思路，并为肿瘤免疫治疗药物研发提供新的候选靶分子。

恶性肿瘤严重困扰人类健康。CD8+ 细胞毒性T淋巴细胞（CTL）在清除肿瘤中起到了重要作用，而在肿瘤微环境中CD8+ T细胞发生功能耗竭，导致肿瘤不能被清除。已有的动物模型和临床病人的研究表明，耗竭CD8+ T细胞上表达抑制性受体Tim-3，并且阻断Tim-3可以恢复耗竭CD8+ T细胞的功能。Tim-3作为肿瘤免疫治疗的热点靶分子受到极大关注。本课题使用基因敲除小鼠证明了Tim3负调控T细胞抗肿瘤功能，并筛选到两个靶向Tim3的小分子抑制，可以促进T细胞抗肿瘤功能。发现消化系统肿瘤患者sTim-3的水平显著升高，并证实人sTim-3主要由ADAM10和ADAM17介导产生，体内外功能研究发现，sTim-3显著抑制T细胞分泌细胞因子，影响肿瘤微环境促进荷瘤小鼠体内肿瘤细胞的生长。本研究首次发现Tim3和sTim-3促进免疫抑制介导肿瘤免疫逃逸的作用，为揭示肿瘤发生机制提供了新思路，同时为免疫检查点治疗提供了新机制。