去酰基化酶sirtuins对IgA+ B细胞介导肠癌免疫抑制的调控研究

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。

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.