IL-36β促进Tc9细胞分化及其肿瘤过继性免疫治疗作用的机制

以对肿瘤杀伤活性较强的Tc1分化类型为导向的肿瘤过继性T细胞治疗，往往因Tc1功能易耗竭而杀伤效应难以持久；最近发现Tc9细胞对肿瘤的抑制作用持久且显著。.我们前期的研究初步发现，IL-36β可显著促进Tc9分化，其诱导的Tc9对肿瘤具有更突出的过继性免疫治疗效果。本项目拟在此基础上，通过体外和动物实验：阐明IL-36β可通过上调BATF、BATF3等转录因子，及激活STAT6和NF-κB信号，促进Tc9分化；揭示Tc9分化以糖酵解途径为主要代谢特征，IL-36β可通过激活mTORC1/HIF1α信号，促进Tc9分化所需的糖酵解代谢途径；证实与经典条件下诱导的Tc9相比，IL-36β促进分化的Tc9细胞在体内具有更好的存活特性、增殖能力和肿瘤杀伤效应；从而为开展诱导具有优良性能的Tc9细胞、并以其分化类型为导向的肿瘤过继性免疫治疗，探索较好的技术方法和奠定坚实的理论基础。

Adoptive T cell therapies targeting Tc1 differentiation types with strong cytotoxic activity are often difficult to sustain due to the exhaustion of Tc1 function. Recently, it has been found that Tc9 cells have a lasting and significant inhibitory effect on tumors..Our previous studies preliminarily found that IL-36β can significantly promote Tc9 differentiation, and its induced Tc9 has a more prominent adoptive immunotherapeutic effect on tumors. On this basis, through in vitro and animal experiments, this project aims to 1) clarify that IL-36β can promote Tc9 differentiation by up-regulating transcription factors such as BATF and BATF3, activating STAT6 and NF-kappa B signals; 2) reveal that glycolysis pathway is the main metabolic feature of Tc9 differentiation, and IL-36β can promote the glycolysis pathway required for Tc9 differentiation by activating mTORC1/HIF1 alpha signals; 3) 3) substantiate that compared with Tc9 induced by the traditional cytokine condition including TGF-β and IL-4, Tc9 synergistically drived by IL-36β has better long-term survival, proliferation and killing effect on tumors in vivo. Thus develop a good technical method and lay solid theoretical foundation for the development of adoptive cell immunotherapy for tumors guided by the type of Tc9 differentiation induced by IL-36β.