实体肿瘤γδT细胞新型免疫疗法的基础理论和关键技术研究

实体肿瘤的高度异质性和免疫抑制性微环境是造成免疫细胞在实体肿瘤微环境中功能耗竭和目前免疫疗法对实体肿瘤应答率不高的主要原因。γδ T细胞是一群对肿瘤细胞具有早期免疫监视和非MHC限制性识别、杀伤的特殊T细胞。本项目拟通过研究γδ T细胞对肿瘤相关抗原“一对多”和“膜异位”识别模式的机制，鉴定γδT细胞识别的肿瘤细胞表面抗原分子；通过研究γδ T细胞在实体肿瘤微环境中功能耗竭的分子机理和调控机制，鉴定调控γδ T细胞功能的新型识别靶点，找到能够促进γδ T细胞杀伤肿瘤细胞活性的免疫调控小分子，或者通过基因工程手段与免疫检查点抗体组合，优化细胞治疗方案；基于γδ T细胞对肿瘤细胞非MHC限制性识别的特性，建立一种针对实体肿瘤的新型、通用型CAR-γδT细胞，解决实体肿瘤异质性和异体细胞免疫治疗问题，为实体瘤及异体细胞治疗提供理论依据和实验基础。

The high heterogeneity and immunosuppressive microenvironment of solid tumors are two major reasons for the exhaustion of immune cells in the tumor microenvironment and the low response rate of immunotherapy to solid tumors. γ δ T cells are a group of special T cells with early immune monitoring and non-MHC recognition and killing activity to tumor cells. This project aims to identify γ δ T cell-recognized tumor antigen molecules by exploring the mechanism of "one to many" and "ectopic membrane antigen" recognition pattern of tumor related antigens by γ δ T cells; We will also study the molecular regulation mechanism of function exhaustion of γ δ T cells in the solid tumor microenvironment to identify new recognition targets that can regulate the function of γ δ T cells. Then, we will screen small immune regulation molecules that can promote the function of γ δ T cells killing activity to tumor cell, and establish a genetically engineered combination of γ δ T cells and immune checkpoint antibodies to optimize the regime of cell therapy. Based on the non-MHC restriction of γ δ T cells recognition to tumor cells, we will develop a novel universal CAR-γ δ T cells for solid tumor to solve the problems of solid tumor heterogeneity and allogeneic cell immunotherapy, providing theoretical and experimental basis for solid tumor and allogeneic cell therapy.