CD19lowCD138+浆细胞促进胰腺导管腺癌吉西他滨化疗抵抗形成的作用及机制研究

吉西他滨化疗抵抗是威胁胰腺导管腺癌（PDAC）病人生命的主要原因之一，但其的形成机制尚不明确。我们前期研究发现一群高表达IgG的CD19lowCD138+浆细胞在接受吉西他滨化疗的PDAC病人和小鼠模型中特异扩增，且耗竭该群细胞能显著增强肿瘤对化疗的敏感性。机制研究显示该群细胞能诱导巨噬细胞的M2b极化。我们推测该群细胞可能通过诱导IgG介导的TAMs的M2b极化抑制化疗重激活的抗肿瘤免疫反应，从而促进肿瘤化疗抵抗的形成。本项目拟在PDAC病人和自发胰腺癌小鼠模型中明确CD19lowCD138+浆细胞与肿瘤化疗抵抗的相关性；用CD19-cre；Prdm1 floxp/floxp小鼠模型特异阻断该群细胞的生成来验证其的促化疗抵抗特性；通过体外共培养实验阐明该群细胞促化疗抵抗的分子机制。本项目首次探讨肿瘤浸润B细胞促进PDAC吉西他滨化疗抵抗形成的机制，为临床克服胰腺肿瘤化疗抵抗提供了新思路。

One of the major challenges that threaten pancreatic ductal adenocarcinoma (PDAC) patients’ life is the chemoresistance to gemcitabine. However, the mechanisms responsible for the development of this chemoresistance remain poorly-defined. In the previous study, we identified a population of CD19lowCD138+ plasma cells that highly express IgG and undergo specific expansion in PDAC patients and mouse models treated with gemcitabine. More importantly, the exhaustion of these cells sensitizes pancreatic tumors to gemcitabine in mouse models. Mechanistically, CD19lowCD138+ plasma cells can induce the M2b polarization of macrophages. Accordingly, we hypothesize that CD19lowCD138+ plasma cells drive the M2b polarization of TAMs by IgG, which inhibits anti-tumor immune responses reactivated by gemcitabine, and thus contributes to the development of the chemoresistance of pancreatic tumors. To verify the hypothesis, we will firstly examine the correlation between the chemoresistance of PDAC to gemcitabine and CD19lowCD138+ plasma cells in PDAC patients and spontaneous pancreatic cancer mouse models. And then, we will validate the roles of CD19lowCD138+ plasma cells in promoting the chemoresistance of pancreatic tumors to gemcitabine in the CD19-cre;Prdm1floxp/floxp mouse model, where the generation of these cells is specifically blocked. Finally, we will explore the molecular mechanism by which CD19lowCD138+ plasma cells promote the chemoresistance of PDAC to gemcitabine in an in-vitro coculture system. Collectively, we first explore the mechanism responsible for promoting the chemoresistance of PDAC to gemcitabine by tumor-infiltrating B cells, which provides a new thought to overcome the chemoresistance to gemcitabine in PDAC patients.