二级淋巴器官中基质细胞“重塑”在CD8+T细胞抗瘤免疫应答缺陷中的作用及机制研究

Elucidation of anti-tumor immune deficiency is the key premise for novel immunotherapy design agains tumor.Based on our preliminary findings together with the knowledge from the publicaiton, we proposed: reduced CCL19 and/or CCL21 production in remodelled FRCs derived from secondary lymph organisms (SLOs), such as lymph node and spleen, which affects the entering of na?ve CD8-positive T cells into T cell zone and their activation, contributes to the anti-tumor immune deficiency in tumor-bearing individuals.In the present, we will determine the producion of CCL19 and CCL21 in the stromal cells derived from SLOs and its effect on the localization of CD8-positive cells in T cell zone and their activation through the establishment of tumor-bearing mice models and analyzing the correlation of CCL19/CCL21 expression and T cell localization. Moreover, we will explore the underlying mechanisms of reduced CCL19/CCL21 expression from strom cells in SLOs through several tumor-bearing model in knock-out mice and in vitro experiments. Through this project, we could elucidate the underlying mechanims of microenvironment remodelling inducd anti-tumor immune deficiency, and further understand the cause of anti-tumor immune deficiency, more immportantly it will provide some clues to the design of novel anti-tumor immunotherapy.

阐明机体抗瘤免疫应答缺陷机制是设计新型肿瘤免疫治疗策略的前提和基础。申请者基于前期研究发现和相关文献背景，提出科学假说：在荷瘤状态下，由于机体二级淋巴器官中（SLOs）基质细胞FRCs的"重塑"导致其趋化因子（如CCL21和CCL19）表达下降，从而影响了初始型CD8+T细胞进入T细胞区及其活化，可能是机体抗瘤免疫应答缺陷的重要机制之一。本项目拟通过建立不同的荷瘤模型，结合临床组织标本相关性分析，明确荷瘤状态下SLOs中基质细胞CCL19和CCL21的表达情况及其对CD8+T细胞在SLOs中T细胞区定位和活化的影响；利用基因敲除小鼠和体外实验，阐明荷瘤导致SLOs基质细胞CCL19和CCL21表达障碍的具体机制。通过本项目的研究，有望阐明荷瘤状态下SLOs微环境"重塑"对抗肿瘤免疫应答的影响及其分子机制，深入理解机体抗瘤免疫应答缺陷的具体原因，而且也将为新的肿瘤免疫治疗方案设计提供新思路。

阐明机体抗瘤免疫应答缺陷机制是设计新型肿瘤免疫治疗策略的前提和基础。申请者基于前期研究发现和相关文献背景，提出科学假说：在荷瘤状态下，由于机体二级淋巴器官中（SLOs）基质细胞FRCs的“重塑”导致其趋化因子（如CCL21和CCL19）表达下降，从而影响了初始型CD8+T细胞进入T细胞区及其活化，可能是机体抗瘤免疫应答缺陷的重要机制之一。本项目发现一群新的免疫抑制细胞CD45+EPC，并深入阐明其通过高表达ROS显著抑制CD8+T细胞抗瘤免疫应答，成为导致肿瘤免疫耐受及系统性免疫功能下降的关键因素。通过本项目的研究，阐明了荷瘤状态下SLOs微环境“重塑”对抗肿瘤免疫应答的影响及其分子机制，深入理解机体抗瘤免疫应答缺陷的具体原因，而且也将为新的肿瘤免疫治疗方案设计提供新思路。