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。

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.