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IL-35 Producing B Cells Promote the Development of Pancreatic Neoplasia

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IL-35 Producing B Cells Promote the Development of Pancreatic Neoplasia Author Manuscript Published OnlineFirst on December 29, 2015; DOI: 10.1158/2159-8290.CD-15-0843 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. IL-35 producing B cells promote the development of pancreatic neoplasia Yuliya Pylayeva-Gupta1,3, Shipra Das1, Jesse S. Handler1, Cristina H. Hajdu2, Maryaline Coffre2, Sergei Koralov2, Dafna Bar-Sagi1 1Department of Biochemistry and Molecular Pharmacology; 2Department of Pathology, New York University School of Medicine, New York, NY, 10016, USA 3Present address: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, 27514, USA. Correspondence: Dafna Bar-Sagi, Ph.D., Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, 550 First Avenue, Smilow 201, New York, NY 10016; FAX 646-501-6721; email: [email protected] Keywords: KRas; pancreas; cancer; B cells; Interleukin-10; Interleukin-35 Running title: B cells play a pro-tumorigenic role in pancreatic neoplasia Conflict of interest: The authors have no conflict of interest to disclose. Page 1 of 27 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 29, 2015; DOI: 10.1158/2159-8290.CD-15-0843 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT 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. 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. 2 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 29, 2015; DOI: 10.1158/2159-8290.CD-15-0843 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive disease with a dismal 5- year survival rate of 6% and a poor response to all existing therapies. The development of PDA is initiated by mutations in the KRas oncogene followed by inactivating mutations and deletion of tumor suppressor genes including TRP53, CDKN2A, and SMAD4 (1). The role of these alterations in the initiation and progression of PDA has been attributed to cell-intrinsic processes that are critical for malignant transformation, including the bypass of proliferative barriers, metabolic adaptation and metastatic dissemination. In addition to these genetically-driven cell intrinsic changes, a key pathophysiological aspect of PDA is the recruitment of host immune cells into the tumor microenvironment. Investigations into the functional relevance of discrete tumor infiltrating immune cell subtypes have uncovered a multitude of immunomodulatory mechanisms mediated by recruited cells. For example, tumor associated macrophages and myeloid-derived suppressor cells have been shown to promote pancreatic tumorigenesis through the suppression of anti- tumor immunity via expression of heme oxygenase-1 and arginase, respectively (2-4). CD4+ T cells repress the anti-tumor activity of CD8+ cytotoxic T cells from the onset of pancreatic neoplasia (5). Likewise, regulatory subset of CD4+ T cells promotes progression of pancreatic neoplasia by suppressing anti-tumor T cell immunity in mice immunized with Listeria monocytogenes (6). Furthermore, PDA associated inflammation potentiates differentiation of immune cell subsets, such as Th17 T cells and plasmacytoid dendritic cells, that can enhance tumor cell 3 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 29, 2015; DOI: 10.1158/2159-8290.CD-15-0843 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. growth (7, 8). Significantly, these mechanisms are engaged at very early stages of disease development and represent attractive targets for therapeutic intervention. We have previously shown that the formation of preinvasive lesions known as pancreatic intraepithelial neoplasia (PanIN) is accompanied by the recruitment of B cells into the pancreatic parenchyma (3). In the present study we sought to determine whether this immune cell population plays a role in neoplastic progression. Our findings identify a B cell subset that contributes to pancreatic cancer pathogenesis through a paracrine mechanism that promotes the proliferation of the transformed epithelium. RESULTS To investigate the role of B cells in pancreatic tumorigenesis, we first assessed whether their presence is linked to pancreatic neoplasia in human and mouse. Prominent B cell infiltrates were detected in proximity to human PanIN lesions as well as in pancreata of LSL-KrasG12D;p48Cre (KC) mice (Fig. 1A). Furthermore the implantation of pancreatic ductal epithelial cells expressing oncogenic KRas (KRasG12D-PDEC) into wild-type (WT) pancreata led to the accumulation of B cells in regions adjacent to the newly established neoplastic lesions (Fig. 1A) suggesting an instructive role for the transformed epithelium in B cell recruitment. We reasoned that the infiltration of neoplastic lesions by B cells would be mediated by chemotactic cues with the most relevant being the main B cell chemoattractant CXCL13. Consistent with this postulate, CXCL13 was detected 4 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 29, 2015; DOI: 10.1158/2159-8290.CD-15-0843 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. in the fibroinflammatory stroma surrounding human and mouse PanIN lesions (Fig. 1B and C; and Supplementary Fig. S1A and B), and treatment of mice with anti-CXCL13 blocking antibody resulted in decreased accumulation of B cells in pancreata of KC mice and mice orthotopically implanted with GFP- KRasG12D-PDEC (Supplementary Fig. S1C-F). To further characterize the CXCL13-expressing cell population, qPCR analysis was performed on FACS- sorted cells from pancreata of KC mice. Using the immune marker CD45 and the fibroblast marker CD140 (PDGFR), we found that the expression of CXCL13 was restricted to the fibroblast fraction (CD45-CD140+) of the isolated cells (Fig. 1D). In agreement with this finding, double immunofluorescent staining revealed that CXCL13 expressing cells were positive for the mesenchymal marker vimentin (Fig. 1B and C, insets). Another cell population that could potentially contribute to CXCL13 production is dendritic cells (9). However, we did not detect CXCL13 mRNA in intra-pancreatic dendritic cells (CD45+CD11c+) (Fig. 1D). Together, these results indicate that in the context of evolving pancreatic neoplasia, stromal fibroblasts are induced to secrete CXCL13, thereby promoting the infiltration of B cells into the pancreatic tumor microenvironment. These observations are consistent with recent findings documenting that fibroblast-mediated production of CXCL13 potentiates recruitment of B cells in a prostate cancer model (10). The physiological relevance of this recruitment event is suggested by the fact that anti-CXCL13 treatment of mice orthotopically implanted with GFP-KRasG12D- PDEC resulted in the reduced growth of the orthotopic lesions (Supplementary Fig. S1G and H). 5 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 29, 2015; DOI: 10.1158/2159-8290.CD-15-0843 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. To directly analyze the functional significance of B cells in pancreatic tumorigenesis, GFP-KRasG12D-PDEC were implanted into pancreata of μMT mice which lack functional B cells or syngeneic WT control animals. Analysis of pancreata at 2 weeks post-implantation revealed a significant reduction in the abundance of GFP-KRasG12D-PDEC-derived lesions in μMT mice in comparison to WT mice (Fig. 1E and F). A similar difference was observed at four weeks post-implantation (Supplementary Fig. S2A and B). To determine
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