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 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); 1–9. ©2015 AACR.
See related commentary by Roghanian et al., p. 230.
See related article by Lee et al., p. 256.
See related article by Gunderson et al., p. 270.
Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).
- Received July 10, 2015.
- Revision received December 21, 2015.
- Accepted December 22, 2015.
- ©2015 American Association for Cancer Research.