免疫检验点阻断条件下共生菌对Treg细胞功能和肠道炎症反应的调节机制

肠道共生菌的组成可显著影响免疫检验点疗法在抗肿瘤治疗中的疗效和副作用的发生。我们前期的研究表明双歧杆菌作为一种重要益生菌可在不干扰抗肿瘤治疗疗效的情况下，显著缓解免疫检验点抑制所引起的肠道炎症损伤，并且此炎症缓解效应依赖于肠道固有层定殖的调节性T细胞（Treg）。但目前对于在不同免疫检验点阻断治疗过程中，肠道Treg细胞与共生菌群在炎症状态下的相互作用机制尚缺乏深入理解。在本申请中，我们将利用已建立的肠炎动物模型，结合16S测序分析和免疫细胞代谢及功能检测，研究特定益生菌株对整体共生菌群动态的影响，以及对肠道Treg细胞线粒体代谢和免疫抑制功能的调控。并进一步通过Treg细胞去除技术探索肠道免疫系统炎症状态反馈调节共生菌群组成的机制。本项目将揭示肠道菌群在免疫检验点抗肿瘤治疗中的作用机理，为减弱免疫检验点阻断治疗的副作用，优化其抗肿瘤治疗疗效，提升综合治疗效果提供理论依据。

The gut commensal microbiota affects the efficacy of immune checkpoint-blockade therapy and the change of immune status also affect the composition of commensal microbiota in patients. Our previous work showed that a well-known probiotics, Bifidobacterium, can effectively relieve the gut immunopathology without affecting the anti-tumor immunity of immune checkpoint inhibition. Furthermore, we found this gut inflammatory remission depends on the exist of the regulatory T cell (Treg). However, we still have very little understanding of the interactions between intestinal immune cells and commensal microbiota under the condition of the immune checkpoint inhibition-related colitis. In this application, based on our established colitis mouse model, we will combine 16S sequencing with immune cell metabolism and functional assays to identify the specific strains of probiotics, study the relationship between the function of intestinal Treg cells and the composition of gut microbiota, also explore the role of mitochondrial metabolism in this process. By revealing the regulatory mechanism of commensal microbiota and immune system with immune checkpoint blockade, we will provide new ideas for mitigating the intestinal side effects and improving the overall therapeutic efficacy of immune checkpoint inhibition related therapies.