IL-36/IL-36R信号介导CD8+T细胞抗肿瘤免疫应答的机制

肿瘤微环境中CD8+TILs处于代谢抑制和免疫抑制状态，难以发挥有效的抗肿瘤作用；我们前期的研究工作阐明了IL-36/IL-36R信号能促进CD8+T细胞活化、增强肿瘤特异性CD8+T细胞免疫应答和改变肿瘤微环境，显著抑制肿瘤的生长与转移。.本项目旨在通过临床、体外及动物实验：阐明IL-36/IL-36R信号可通过MyD88、IKK途径激活mTORC1、直接促进CD8+T细胞的生长代谢及其活化，并通过mTORC1诱导DC成熟间接促进CD8+T细胞的活化，来介导CD8+T细胞的抗肿瘤免疫应答；证实内源性“危险信号”IL-36/IL-36R的变化、缺失会影响到CD8+TILs的mTORC1活化、代谢、免疫效应及肿瘤免疫微环境，并与肿瘤的进展密切相关；从而揭示IL-36/IL-36R信号介导CD8+T抗肿瘤免疫应答的机制，为其进一步应用于肿瘤免疫治疗奠定理论基础。

It has been reported that the status of metabolic suppression and immunosuppression blocked the anti-tumor function of CD8+T cells. Previously, we have identifed that IL-36/IL-36R signal could promote CD8+T cell activation, proliferation and cytokine production in vitro and remarkably inhibit tumor progression in vivo through improving tumor-specific CD8+ T cells and transforming tumor microenvironment. .This project aims to explore the mechanism that IL-36/IL-36R signal can promote the metabolism of CD8+T cells, then activate CD8+T cells, and subsequently inhibit tumor progression dependent on analyzing the clinlic sapmles from patients with lung cancer and developing experiments in vitro and in vivo. Our hypotheses are as follows: (1) IL-36/IL-36R signal can directly promote CD8+T cell metabolism by stimulating mTORC1 dependent on MyD88 and IKK and indirectly activate CD8+T cells by inducing DC maturation through stimulating mTORC1. (2) Variation or defect of endogenous “danger signal” IL-36/IL-36R will influence mTORC1 activation, metabolism and immune response of CD8+TILs, shape the tumor microenvironment and correlate with tumor progression.