支链氨基酸通过激活mTORC1信号通路促进Treg细胞分化在结肠癌发生发展中的机制研究

肿瘤微环境中激烈的代谢竞争抑制了免疫细胞对肿瘤细胞的杀伤能力，通过重编程免疫细胞代谢来重塑免疫系统，将为肿瘤治疗带来新希望。据报道，支链氨基酸（BCAAs）限制性饮食抑制多种小鼠肿瘤模型包括结肠癌的生长，而其中机制未明。我们前期研究发现，在敲除了去琥珀酰化修饰酶Sirt7的小鼠中，BCAAs累积后激活mTORC1信号通路，影响了T细胞向不同亚群分化的能力。我们推测，琥珀酰化修饰抑制BCAAs分解代谢通路相关酶的酶活，导致BCAAs分解代谢受阻，BCAAs累积并激活mTORC1信号通路，促进肿瘤微环境中Treg细胞分化维持免疫抑制，促进肿瘤生长。为验证此假说，我们在本项目中将结合细胞、小鼠模型和人结肠癌标本，深入研究BCAAs-mTORC1-T细胞分化这一信号轴在T细胞抗肿瘤免疫中的功能，阐明限制性BCAAs饮食抑制结肠癌的分子机制，从重编程T细胞氨基酸代谢角度为肿瘤治疗提供新视角。

It was first recognized during the early 1920s that tumors utilize glucose at a high rate and produce lactate in a process termed the ‘Warburg effect’. This metabolic program differs from that used by normal tissues in that nutrients are not readily oxidized in mitochondria for maximal ATP generation, but are instead conserved for biosynthesis of nucleic acids, lipids, and amino acids to support cell growth. High levels of glycolytic activity coupled with poor angiogenesis in tumor cells lead to glucose depletion and accumulation of waste products within the tumor microenvironment. .Like tumor cells, T cell metabolism is under tight regulation in an immune response to promote effector T cell expansion and function. Naïve T cells are quiescent cells that require relatively small amounts of glucose, amino acids, and fatty acids to maintain basic energetic and biosynthesis demands. Encountering with antigen triggers T cell activation and differentiation into effector T cells (Teff cells), which rely on a high intake of glucose and amino acids to support proliferation and effector functions, such as cytotoxicity and cytokine production. After pathogen clearance, T cells return to a primarily catabolic metabolism as long-lived memory cells. The pathways that control these metabolic transitions including the Phosphatidylinositide 3 Kinase (PI3K)/Akt/ Mammalian Target of Rapamycin (mTOR) signaling pathways. .Thus, T cell metabolism has a central role in supporting and shaping immune responses and have a key role in antitumor immunity. T cells with limited access to nutrients therefore face dual metabolic jeopardy, which may impair the efficacy of T cell-mediated anti-tumor efficiency. A better understanding of the molecular mechanisms that manifest in the immunosuppressive tumor microenvironment is crucial for developing more efficacious immunotherapies. However, how the tumor microenvironment modifies metabolic and functional pathways in T cells and how these changes may uncover new targets and challenges for cancer immunotherapy are largely understood..It is now appreciated that modulating branched-chain amino acids (BCAAs) catabolism during carcinogenesis enhances mTORC1 activity and promotes tumor development and progression. Dietary BCAAs intake in humans also correlated with cancer mortality risk. Our preliminary data and clues from references have implied that branched-chain amino acid interfering with T cell metabolic reprogramming pathways can impair T cell responses. .We propose that BCAAs – mTORC1 ‘metabolic fitness’ in T cell differentiation is central to effective antitumor immunity. In this project, we will combine in vitro and in vivo assay to modulate BCAAs accumulation in T cells and to investigate the consequence in regulating tumor burden and overall survival.