胆固醇代谢调控T细胞肿瘤免疫应答的机制研究

胆固醇代谢除了调控代谢组织外，还会在生理病理条件下直接调控免疫系统的功能，然而其中的分子机制却远未阐明。我们的前期研究表明胆固醇水平的提高可以增强T细胞的肿瘤杀伤功能（Nature 2016，通讯作者）。在此基础上，本项目将深入研究胆固醇代谢对杀伤性T细胞抗肿瘤功能的调控机制。我们将利用新发展的甾醇组学等技术研究杀伤性T细胞的胆固醇代谢特征；利用各类生化及成像技术研究胆固醇代谢对杀伤性T细胞增殖和杀伤过程的调控作用；结合肿瘤模型和病人数据研究胆固醇代谢重编程对肿瘤微环境中杀伤性T细胞发生功能耗竭的影响；最后利用CRISPR-Cas9技术改造CAR-T细胞的胆固醇代谢程序，优化其抗肿瘤功能，发展新的细胞治疗产品。本项目紧扣糖脂代谢这一主题，在免疫系统中交叉研究胆固醇代谢的功能，阐明其在生理病理条件下的变化规律并由此发展新的肿瘤免疫治疗方法，具有很好的理论创新和应用前景。

Cholesterol metabolism not only regulates metabolic tissues but also immune system under physiological and pathological conditions. However, little is known about the functional roles of cholesterol metabolism in immune system. Our earlier study demonstrates that increasing cholesterol level can potentiate tumor killing function of T cells (Nature 2016, corresponding author). In this project, we will continue to do more mechanistic studies of T-cell cholesterol metabolism in the process of tumor killing. Here we will focus on killer T cell, a major force of antitumor immunity. Firstly, using a newly developed sterol-omics system, we will provide a whole picture of sterol profile of killer T cells. Secondly, we will use biochemical and imaging technologies to study how cholesterol metabolism regulates T-cell killing process. Thirdly, combining preclinical tumor models and patient data, we will study the roles of cholesterol metabolism reprogramming in tumor-induced T cell exhaustion. Finally, we will use CRISPR-Cas9 technology to edit cholesterol metabolic program of CAR-T cells to improve antitumor function, thus developing new therapeutic products. This project fits well within the major scope of the “Sugar and lipid metabolism” Key Research Project of NSFC. It represents a good interdisciplinary study of metabolism and immunology. The execution of this project can lead to new concepts of immunometabolism and new products of cancer immunotherapy.