免疫稳态失衡在炎癌转化的开关机制-免疫负性调控因子SIRPα在免疫球蛋白受体pIgR免疫背叛中的调控

Inflammation has become an important pathological features of tumor development, more and more scientists focus on double-edged sword of immune regulation in tumorigenisis, among them, the negative regulation signal in immune cell activation process is essential for controlling the strength of immune response and maintaining its stability. This project is a new perspective focus on the interaction of immune homeostasis imbalance and the immune betrayal, to start from the regulatory mechanisms of SIRPα which is the negative regulatory molecules in immune homeostasis, that switch on immunoglobulin receptor pIgR-mediated immune betrayal in epithelial cells, and exploration of the negative immune factor SIRPα in the manipulation of immune defense to immune betrayal that the dynamic transformation of the “on / off " mechanism, and to clarify the “on / off” mode which drives pIgR-mediated EMT from inflammation to cancer, this findings is expected from new perspective to interpret the role of negative regulation of immune homeostasis in regulation of dynamic process of the transformation of inflammation to cancer, and is of great significance for re-examine the immune steady state function of negative regulatory molecules in tumorigenesis.

炎症已经成为肿瘤发生发展的重要病理特征，越来越多的科学家将目光集中到肿瘤发生过程中的免疫调节的两面性，其中，免疫细胞活化过程中的负性调节信号对控制免疫应答强度及维持自稳至关重要。本课题拟从免疫稳态失衡与免疫背叛两个全新视角出发，以免疫稳态负性调控分子SIRPα启动上皮细胞组织中免疫球蛋白受体pIgR介导的免疫背叛调控机制入手，探究免疫负性因子SIRPα操控免疫防御至免疫背叛动态转化的“开/关”机制，阐明驱动pIgR炎癌转化的开/关模式，研究结果将有望从免疫稳态负性调控这一全新视角诠释炎癌转变的动态过程，对重新审视免疫稳态负性调控分子在肿瘤发生发展中功能的认识意义重大。

炎症已经成为肿瘤发生发展的重要病理特征，越来越多的科学家将目光集中到肿瘤发生过程中的免疫调节的两面性，其中，免疫细胞活化过程中的负性调节信号对控制免疫应答强度及维持自稳至关重要。本课题从免疫稳态失衡与免疫背叛两个全新视角出发，聚焦“免疫稳态负性调控分子”和“多聚免疫球蛋白受体”，探究pIgR促进肿瘤恶性转化的调控机制、潜在的临床转化治疗价值，探索SIRPα操控免疫防御至免疫背叛动态转化的“开/关”机制，揭示SIRPα在pIgR免疫背叛发生过程中的调节作用。课题参与团队通过四年的密切配合和联合攻关，多项技术及多层次研究工作的同步开展与交叉进行，我们圆满完成了课题的预期目标。揭示了SIRPα参与调控肿瘤微环境中巨噬细胞表型“转换”、调控微环境中髓系细胞的分布，胆汁酸的代谢等多个环节调节肿瘤生长；多聚免疫球蛋白受体pIgR激活经典免疫受体相关通路，显著促进肿瘤生长，与肝癌预后不良密切相关；更为重要的是，我们明确了SIRPα介导免疫稳态失衡介导pIgR免疫背叛，促进肿瘤发展。上述研究发现了数个新生物标志物、新靶向策略，研究结果丰富了天然免疫学、肿瘤免疫学及肿瘤治疗学的研究内涵，充分诠释了免疫稳态框架下负性调控因子在“炎癌链”发生发展中作用模式。对重新审视免疫稳态负性调控分子在肿瘤发生发展中功能的认识意义重大，对靶向免疫稳态负性系统、克服炎-癌转化的抗肿瘤策略提供契机拓辟新径。.相关工作成果在包括J Exp Med、Hepatology、Clin Cancer Res、Cancer Res、Oncogene、European Journal of Immunology等国际著名期刊发表SCI收录论文19篇，申请国内发明专利1项，培养博士14名，硕士3名。