KLRG1调控肿瘤环境中T细胞免疫功能的机制研究

在抗肿瘤免疫过程中，T细胞效应功能受“免疫检查点”信号负向调控，发现免疫检查点有助于肿瘤免疫靶向新药的研发。KLRG1作为潜在的免疫检查点，在肿瘤环境中对T细胞免疫功能的调控机制目前尚无报道。我们发表的成果表明：KLRG1可抑制肿瘤环境T细胞增殖及效应功能。预实验亦显示：KLRG1可与外源性N-Cadherin结合，进而胞内募集SHIP1，通过影响细胞周期蛋白和效应细胞因子的表达诱导肿瘤环境T细胞耗竭。据此提出假设，KLRG1可能通过SHIP1/AKT/p21通路抑制T细胞增殖及通过 SHIP1/IFN-γ/miRNA155/SHIP1环路负向调控T细胞效应功能。本课题拟阐明KLRG1在肿瘤环境中调控T细胞免疫功能的分子机制，并通过体内动物试验验证靶向KLRG1治疗肿瘤的可行性及效果。本项目内容均属首次阐述，所得结果有助于开启对肿瘤环境中KLRG1的认识，为新型免疫靶向药物研发提供基础。

In the process of antitumor immunity, the function of effector T cells was suppressed by inhibiting signals, the so-called immune checkpoints. Identifying new immune checkpoints contributes to the development of tumor-specific target agents. Our published study has demonstrated that KLRG1 (The Killer cell Lectin-like Receptor G1) may inhibit the proliferation and effector function of T cell. Our further preliminary study also showed that exogenous N-Cadherin initiated a KLRG1-dependent signaling to recruit SHIP1 in the cell. This effect can regulate the expression of cyclin and cytokine and finally induce the depletion of T cells in the tumor environment. Based on the previous findings, we hypothesize that KLRG1 may affect the proliferation of T cells by the “SHIP1-AKT-P21” signal pathway; and that KLRG1 may inhibit the function of effector T cells through the loop signal pathway “SHIP1-IFN-γ-miRNA155-SHIP1”. The future research aims to explore the further elaborate the molecular mechanism of KLRG1 in the regulation of the immune function of T cells. Another aim of this research is to evaluate the feasibility and outcomes of KLRG1 as a target therapy in immunodeficient mouse models. The future findings may update the knowledge of the roles of KLRG1 in tumor environment, and provide potential new targets for tumor immunotherapy.