自身抗体PR3-ANCA通过诱发血管炎症促进肝癌进展的机制研究

Tumor development is closely related to the abnormal immune response. B cells and antibody-mediated humoral immune responses are important components of the tumor immune microenvironment. Our previous study found that B cells accumulated in hepatocellular carcinoma (HCC) and differentiated into IgG-secreting plasma cells. Our recent studies have shown that tumor-associated B cells secreted PR3-ANCA in HCC. Besides, PR3-ANCA-activated neutrophil produced neutrophil extracellular traps (NETs) and induced vascular endothelial cell (HUVEC) necrosis in vitro. In line with these, we also observed the elevated serum PR3-ANCA level is closely related to vascular inflammation and postoperative recurrence in HCC. Based on these results, we hypothesize that PR3-ANCA activates neutrophils to release NETs via FcγR-dependent pathway, which induces vascular inflammatory injury and promotes HCC vascular invasion. This project intends to reveal the mechanisms of PR3-ANCA-induced vascular inflammation and tumor progression though clinical data analysis and combine in vitro and in vivo experimental models, and to explore the function of ANCA-induced vascular inflammation in tumor progression by combining mouse tumor model and vasculitis disease model. The results will not only help us better understand the tumor-related autoimmune response, but also provide a theoretical basis for developing new cancer prevention and treatment strategies based on B cell and humoral immune response.

肿瘤的发生发展与异常的免疫应答密切相关，B细胞及抗体介导的体液免疫是肿瘤免疫微环境中的重要组分。我们前期研究发现B细胞在肝癌（HCC）中聚集并呈现向分泌IgG的浆细胞分化趋势，我们新近研究表明HCC中B细胞高分泌自身抗体PR3-ANCA，体外实验证实PR3-ANCA能够快速激活中性粒细胞释放中性粒细胞胞外诱捕网（NETs）并诱发血管内皮细胞HUVEC坏死；与此一致，HCC患者血浆中PR3-ANCA水平显著升高并与血管侵犯及术后复发密切相关。基于以上前期结果，我们猜想HCC中PR3-ANCA通过FcγR途径激活中性粒细胞释放NETs，进而诱发血管炎性损伤并促进肿瘤血管侵犯。本项目拟充分利用临床资料分析、体外实验模型、同时结合小鼠原位成瘤及血管炎症模型来深入研究PR3-ANCA诱发血管炎症及促进HCC血管侵犯的机制，所得结果将为开发基于B细胞及体液免疫的新型肿瘤防治手段提供理论基础。

B淋巴细胞是多种实体瘤免疫微环境中的重要组分，然而B细胞及其介导的体液免疫反应影响肿瘤发展的机制尚不清楚。我们前期研究发现肝癌浸润B细胞能够高分泌IgG，但这些IgG识别何种抗原却依然未知。我们新近研究结果表明：肝癌浸润B细胞分泌的抗体能够特异识别自身抗原PR3，与此结果一致，肝癌病人血浆中抗PR3自身抗体水平显著升高并与患者血管侵犯密切相关。以此为基础，本项目采用了体内外实验模型来研究肝癌中抗PR3自身抗体的产生机制，并结合实验模型及临床数据来阐明其生物学功能及临床意义。所得结果不仅有助于我们更深入地认识肿瘤相关体液免疫反应，更可为研制以B细胞为靶标的新型肿瘤防治策略提供理论基础。