嵌合抗原受体抗肿瘤功能的结构基础

嵌合抗原受体（chimeric antigen receptor，CAR）修饰T细胞（CAR-T）疗法在血液肿瘤治疗中取得了巨大成功，但对实体瘤的疗效却不理想。为设计新一代CAR以提高实体瘤疗效，我们需了解CAR发挥功能的分子机制，尤其是结构基础。本项目将先利用核磁共振研究CAR胞内信号区结构及膜脂环境对结构的调控作用；然后进一步研究其结构动态性；同时利用定量质谱研究CAR被肿瘤抗原活化后的磷酸化模式；最后利用肿瘤免疫学手段验证关键结构位点对CAR抗肿瘤功能的调控机制。申请人从事核磁共振研究已有20年，近来系统性地研究了T细胞关键免疫受体的活化机制；所在研究组在T细胞抗原免疫应答领域做出了原创性贡献（Nature 2013; Nature 2016），建立了多种免疫学、生物化学和生物物理学研究体系。本项目的开展将为CAR的优化设计提供理论依据，为CAR-T疗法在肿瘤治疗中的应用提供新思路。

Chimeric antigen receptor (CAR)-engineered T cell (CAR-T) therapy has achieved unprecedented success in the treatment of hematological malignancies. However, CAR-T therapy shows limited effect in treating solid malignancies. In order to design a new generation CAR to improve its clinical applications, it is necessary to understand the molecular mechanism of the antitumor function of CAR, especially the structural basis. In this project, we will first use Nuclear Magnetic Resonance (NMR) Spectroscopy to study the structures of CAR signaling modules and the regulation of CAR structures by lipids. Paramagnetic Relaxation Enhancement (PRE) measurement and other technologies will be used to study the structural dynamics of CAR. To further understand CAR signaling, we will use quantitative Mass Spectrometry (qMS) to study the phosphorylation programs of CAR upon the activation by tumor antigens. Lastly, we will investigate how CAR function is regulated by its structure by tumor immunology methods. The applicant has been working with NMR for 20 years. She is now systematically studying the activation mechanism of key immunoreceptors. The research group that the applicant belongs to has made important original contributions in the T-cell immunology field and has established various technologies of immunology, biochemistry and biophysics (Nature 2013; Nature 2016). The accomplishment of this project will provide new theoretical basis for CAR design, and new insights into the application of CAR-T therapy in treating cancers.