IL35-Producing B Cells Promote the Development of Pancreatic Neoplasia

Cancer Discov. 2016 Mar;6(3):247-55. doi: 10.1158/2159-8290.CD-15-0843. Epub 2015 Dec 29.

Abstract

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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism*
  • Biomarkers
  • Carcinoma, Pancreatic Ductal
  • Cell Transformation, Neoplastic / immunology*
  • Cell Transformation, Neoplastic / metabolism*
  • Disease Models, Animal
  • Humans
  • Immunohistochemistry
  • Interleukins / biosynthesis*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Mice
  • Mice, Knockout
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Phenotype

Substances

  • Biomarkers
  • Interleukins
  • interleukin-35, human

Supplementary concepts

  • Pancreatic Carcinoma