IL35-Producing B Cells Promote the Development of Pancreatic Neoplasia.
IL35-Producing B Cells Promote the Development of Pancreatic Neoplasia.
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DOI：
10.1158/2159-8290.cd-15-0843
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发表时间：
2016-03
期刊：
影响因子：
28.2
通讯作者：
Bar-Sagi D
中科院分区：
文献类型：
--
作者：
Pylayeva-Gupta Y;Das S;Handler JS;Hajdu CH;Coffre M;Koralov SB;Bar-Sagi D
胰腺导管腺癌(PDA)的一个显著特征是大量的纤维炎症反应，其特征是免疫细胞和间充质细胞的募集以及随之而来的促进肿瘤形成的微环境的建立。在这里，我们报告了B细胞在人胰腺上皮内瘤变(Panin)和PDA病变中的显著存在，以及在小鼠由K-RAS驱动的致癌胰腺肿瘤中。在B细胞缺陷小鼠(μMT)中，携带致癌K-RAS基因的原位胰腺肿瘤的生长受到显著影响，这种生长缺陷可以通过重建CD1dHighCD5+B细胞亚群来挽救。B细胞的促肿瘤作用是通过其表达IL-35来实现的，其机制涉及IL-35介导的刺激肿瘤细胞增殖。我们的结果确认了以前未知的产生IL-35的CD1dHighCD5+B细胞在胰腺癌发病机制中的作用，并强调了B细胞/IL-35轴作为治疗靶点的潜在意义。
A salient feature of pancreatic ductal adenocarcinoma (PDA) is an abundant fibroinflammatory response characterized by the recruitment of immune and mesenchymal cells and the consequent establishment of a pro-tumorigenic microenvironment. Here we report the prominent presence of B cells in human pancreatic intraepithelial neoplasia (PanIN) and PDA lesions as well as in oncogenic K-Ras-driven pancreatic neoplasms in the mouse. The growth of orthotopic pancreatic neoplasms harboring oncogenic K-Ras was significantly compromised in B cell-deficient mice (μMT), and this growth deficiency could be rescued by the reconstitution of a CD1dhighCD5+ B cell subset. The pro-tumorigenic effect of B cells was mediated by their expression of IL-35 through a mechanism involving IL-35-mediated stimulation of tumor cell proliferation. Our results identify a previously unrecognized role for IL-35-producing CD1dhighCD5+ B cells in the pathogenesis of pancreatic cancer and underscore the potential significance of a B cell/IL-35 axis as a therapeutic target.