共刺激信号TIM-1促进CD8+T细胞抗肿瘤免疫应答及其作用机制

Tumor immune suppression is a main obstacle for cancer immunotherapy. Thus, it is important to find novel targets for reversing immunosuppression and enhancing anti-tumor immune response. TIM-1 is an important member of the T cell immunoglobulin mucin gene family. Our preliminary data show that radio frequency ablation (RFA) could promote T cell infiltrate into distant tumor and up-regulate TIM-1 expression on CD8+T cells. Moreover, we find agonistic TIM-1 mAbs enhanced anti-tumor immune responses..Based on our previous data, we hypothesize that TIM-1 is an important costimulatory molecule promoting CD8+ T cell-mediated antitumor immune responses. In this proposal, we aim to further investigate the clinical significance of TIM-1 expression in tumor infiltrating CD8+T cells in human colorectal cancer tissues after RFA therapy eliciting anti-tumor response in cancer patients. We will also study the underlying mechanism of the transcription factors, T-bet and Eomes, in regulating TIM-1 expression in CD8+T cells. We will then determine whether agonistic TIM-1 mAbs synergize with RFA to promote antitumor immune responses and reveal the role of mTORC1 signal pathway in regulating the immune function of TIM-1. In addition, the TIM-1 conditional knockout mice and g100-pmel-1 system will be used to determine the contribution of TIM-1 in CD8+T cells mediated antitumor immunity against colorectal cancer in vivo. Our study will elucidate the mechanism by which TIM-1 regulates CD8+T cell-mediated anti-tumor immune responses and establish TIM-1 as an important target for enhancing antitumor immunity.

免疫抑制是肿瘤免疫治疗需要解决的关键问题。寻找逆转免疫抑制和增强抗肿瘤免疫应答的新靶点尤为重要。TIM-1是T细胞免疫球蛋白黏蛋白结构域相关分子家族的重要成员。我们已发现激活抗肿瘤免疫应答可上调TIM-1在肿瘤浸润CD8+T细胞的表达，且激发型TIM-1抗体能增强机体抗肿瘤免疫应答，但作用机制尚未明确。.鉴此，我们提出TIM-1促进CD8+T细胞抗肿瘤免疫应答重要共刺激信号的假说。本课题将研究激活抗肿瘤免疫应答后TIM-1在结直肠癌浸润CD8+T细胞上的表达及意义；探索T-bet/Eomes调控CD8+T细胞表达TIM-1的机制；评价肿瘤射频消融协同TIM-1单抗联合治疗的疗效；揭示mTORC1信号通路介导TIM-1的免疫功能；应用条件性TIM-1敲除小鼠模型及g100-pmel-1系统证实TIM-1介导的CD8+T细胞抗肿瘤免疫应答效应。旨在建立以TIM-1为靶点的肿瘤免疫治疗新模式。

免疫抑制是肿瘤免疫治疗需要解决的关键问题。寻找逆转免疫抑制和增强抗肿瘤免疫应答的新靶点尤为重要。TIM-1是T细胞免疫球蛋白黏蛋白结构域相关分子家族的重要成员。我们已本课题证实在结直肠癌浸润CD8+T细胞中，TIM-1表达水平较癌旁组织显著升高；在RFA肿瘤治疗模型中我们也发现，消融后第3天，肿瘤浸润CD8+T细胞中TIM-1表达水平较未消融组显著上调。同时我们将TIM-1构建到CAR-T载体中，结果表明，TIM-1信号可以显著增强CAR-T细胞的IL2的分泌。TIM-1单抗调节CD8+T细胞抗肿瘤免疫应答中的作用及分子机制研究仍在进行中。.项目组围绕射频消融联合PD-1靶向干预治疗开展了系列研究。项目组发现RFA治疗后期可引起肿瘤浸润T细胞活化后失能、Treg与MDSCs扩增、Th1/Th2应答转化、以及PD-1/PD-L1表达上调等肿瘤微环境免疫抑制的现象，该现象也提示免疫干预的重要价值。RFA后开始使用PD-1单抗阻断，可显著增强肿瘤浸润T细胞的浸润数量及效应功能，表现出较好的联合治疗效果。项目组还进行了胃癌肿瘤微环境内肿瘤浸润淋巴细胞和三级淋巴结构的研究、MicroRNA-203介导Bmi-1调控肝癌细胞增殖的机制研究、PD-L1在卵巢癌组织中的表达及其与PARP抑制剂协同抗肿瘤作用机制研究。