Pylayeva-Gupta Yuliya, Das Shipra, Handler Jesse S, Hajdu Cristina H, Coffre Maryaline, Koralov Sergei B, Bar-Sagi Dafna
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
Department of Pathology, New York University School of Medicine, New York, New York.
Cancer Discov. 2016 Mar;6(3):247-55. doi: 10.1158/2159-8290.CD-15-0843. Epub 2015 Dec 29.
A salient feature of pancreatic ductal adenocarcinoma (PDAC) is an abundant fibroinflammatory response characterized by the recruitment of immune and mesenchymal cells and the consequent establishment of a protumorigenic microenvironment. Here, we report the prominent presence of B cells in human pancreatic intraepithelial neoplasia and PDAC lesions as well as in oncogenic Kras-driven pancreatic neoplasms in the mouse. The growth of orthotopic pancreatic neoplasms harboring oncogenic Kras was significantly compromised in B-cell-deficient mice (μMT), and this growth deficiency could be rescued by the reconstitution of a CD1d(hi)CD5(+) B-cell subset. The protumorigenic effect of B cells was mediated by their expression of IL35 through a mechanism involving IL35-mediated stimulation of tumor cell proliferation. Our results identify a previously unrecognized role for IL35-producing CD1d(hi)CD5(+) B cells in the pathogenesis of pancreatic cancer and underscore the potential significance of a B-cell/IL35 axis as a therapeutic target.
This study identifies a B-cell subpopulation that accumulates in the pancreatic parenchyma during early neoplasia and is required to support tumor cell growth. Our findings provide a rationale for exploring B-cell-based targeting approaches for the treatment of pancreatic cancer.
胰腺导管腺癌（PDAC）的一个显著特征是丰富的纤维炎症反应，其特点是免疫细胞和间充质细胞的募集以及随之形成的促肿瘤微环境。在此，我们报告B细胞在人胰腺上皮内瘤变和PDAC病变以及小鼠致癌性Kras驱动的胰腺肿瘤中显著存在。携带致癌性Kras的原位胰腺肿瘤在B细胞缺陷小鼠（μMT）中的生长明显受损，并且这种生长缺陷可通过重建CD1d(hi)CD5(+) B细胞亚群来挽救。B细胞的促肿瘤作用是通过其IL35的表达介导的，其机制涉及IL35介导的肿瘤细胞增殖刺激。我们的结果确定了产生IL35的CD1d(hi)CD5(+) B细胞在胰腺癌发病机制中以前未被认识的作用，并强调了B细胞/IL35轴作为治疗靶点的潜在意义。
本研究确定了一个在肿瘤形成早期积聚在胰腺实质中并支持肿瘤细胞生长所必需的B细胞亚群。我们的发现为探索基于B细胞的靶向治疗方法治疗胰腺癌提供了理论依据。
