IL35-Producing B Cells Promote the Development of Pancreatic Neoplasia

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 (μ MT ), and this growth deficiency could be rescued by the reconstitution of a CD1dhiCD5+ 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 CD1dhiCD5+ B cells in the pathogenesis of pancreatic cancer and underscore the potential significance of a B-cell/IL35 axis as a therapeutic target. Significance: 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. Cancer Discov; 6(3); 247–55. ©2015 AACR . See related commentary by Roghanian et al., [p. 230][1] . See related article by Lee et al., [p. 256][2] . See related article by Gunderson et al., [p. 270][3] . This article is highlighted in the In This Issue feature, [p. 217][4] [1]: /lookup/volpage/6/230?iss=3 [2]: /lookup/volpage/6/256?iss=3 [3]: /lookup/volpage/6/270?iss=3 [4]: /lookup/volpage/6/217?iss=3