去酰基化酶sirtuins对IgA+ B细胞介导肠癌免疫抑制的调控研究

Immunosuppression is an important factor in tumor progression, and the regulatory B cells (Bregs) are emerging as a new essential point in this field. Our previous data showed that IgA positive (+) B lymphocytes were abundant in colorectal cancer tissues and correlated to the poor prognosis of patients, which might be a new type of Bregs with plasma cell phenotypes and intestinal specificity. However, the mechanisms underlying the regulatory pattern of IgA+B cells and their formation remain to be extensively elucidated. Our recent data suggest that metabolism associated sirtuins (SIRT) was abnormal in IgA+B cells, and might be a key regulator in the cell differentiation and function. Therefore, by using SIRTs/IgA+B cell deficient mouse model, clinical samples, as well as metabonomics analysis, this project aims to provide a systematic analysis of the molecular mechanisms of B cell differentiation into immunosuppressive IgA+B cells, and clarify the contribution of tumor microenvironment-triggered and SIRTs-related metabolic reprogramming in this process. Based on the SIRTs-IgA+B cells-regulatory axis, this project will reveal the formation and function of immunosuppressive B cell subsets in colorectal cancer in the perspective of immune metabolism, which might be of promising in finding a theory breakthrough in B cell associated tumor immunosuppression, and develop the new treatment strategy against colorectal cancer.

免疫抑制是介导肿瘤进展的重要因素，其中调节性B细胞（Bregs）是该领域的新增点，我们前期发现IgA+B细胞在肠癌组织富集并与疾病进展相关，可能是一类具有肠道组织特异性的浆细胞样Bregs，但关于其抑制性效应模式及形成机制的研究还是空白。我们发现代谢相关的去酰基化酶sirtuins(SIRTs)可能是调控IgA+B细胞生成及抑制性发挥的重要分子。为此，本项目拟通过小鼠结肠癌模型及肠癌患者样本，联合IgA/SIRTs基因工程鼠及免疫代谢分析等技术，系统性解析B细胞分化为IgA+B细胞的分子机制，明确肠道肿瘤微环境联合SIRTs去酰基化介导的代谢重编程对IgA+B细胞分化和免疫抑制功能的调控，及其在肠癌进展中的作用。该项目以SIRTs-IgA+B-免疫调控为主线，从免疫代谢角度解释肿瘤微环境下驱动B细胞亚群免疫抑制形成的机制，以期在理论上获得新突破，在应用上发现新途径。

B 细胞是肿瘤核心免疫网络中强大的、多方面的参与者。我们课题组前期发现IgA+ B细胞是肠癌重要免疫负性调控细胞，并且随着肿瘤进展明显富集。为此，本项目按照既定计划，重点针对IgA+B细胞展开了多维度、系统性研究。项目已完成既定目标，并针对肠癌浸润B细胞进行了拓展研究，获得了肿瘤浸润B细胞的系列成果。包括：(1) 明确了IgA+B 细胞在肠癌进展期富集，并通过抑制CD8+T细胞的杀伤功能促进肠癌进展；(2) 发现了调控IgA+B细胞浸润的微小RNA miRNA15a/16-1，以及促进调节性功能获得的SIRT1分子，表观分子HOTAIR、TET2；(3) 创新性引入饮食与代谢调控，发现模拟禁食饮食通过促进脂肪酸氧化下调IgA+B细胞分化。(4) 解析肠癌浸润B细胞图谱的基础上，发现了介导肠癌免疫抑制的B细胞新亚群LARS B，针对其亮氨酸营养偏好性，提出亮氨酸节律饮食抗癌策略。相关研究成果发表SCI论著共8篇，发表在Immunity, Gastroenterology, Hepatology, Immunology, Frontiers in immunology等免疫学和消化病权威。荣获上海市自然科学二等奖，受邀在国际免疫学大会、中国免疫学全国免疫学会议等国内外重要免疫学及肿瘤学大会发言7次。培养研究生6名，博士后1名。项目针对肠癌B细胞取得的系列研究成果，不仅拓展了肿瘤相关B细胞的基础理论，也为开发基于B细胞的肿瘤免疫新疗法奠定了基础。