Abstract 3822: Immunosuppressive role of mast cells is essential for the tumorigenesis of pancreatic ductal adenocarcinoma (PDAC)

Abstract

Abstract Objectives: Pancreatic ductal adenocarcinoma (PDAC), which is characterized by a dense tumor microenvironment containing a cell rich population, is a relatively common malignancy with a dismal prognosis. Our previous studies using a transgenic spontaneous PDAC mouse model (K-rasG12V mice) revealed an early influx of mast cells into the tumor microenvironment. Further, we found decreased tumor growth when PDAC was implanted into mast cell-deficient Kitw-sh/w-sh mice (Kit−/− mice) compared to wild type C57BL/6 control mice (WT mice). To further assess the role of mast cells in the tumorigenesis of human PDAC, we correlated mast cells infiltration with clinical outcome. Using PDAC mouse models, we explored the immunosuppressive mechanisms of mast cells on PDAC in vivo. Methods: To assess the clinical significance of mast cells, we quantified it in a tissue array of 66 human PDAC samples and correlated the quantities with clinical outcome. Pancreas tissues were obtained from K-rasG12V mice and grouped by stages: chronic pancreatitis (CP, N = 3); pancreatic intraepithelial neoplasia (PanIN, N = 3); and PDAC (N = 3). Normal pancreas tissues (NP, N = 3) were obtained from K-ras wild-type mice. RNA expression of IL-10 and its receptors were determined with a cDNA microarray on an Illumina whole-genome-expression array containing 45 281 probes and confirmed by real-time RT-PCR. Panc-02 PDAC cells were orthotopically implanted into the pancreas of Kit−/− mice and WT mice. In the mast cell reconstitution model, Kit−/− mice received intraperitoneal injections of bone marrow-derived mast cells from of IL-10−/−, PGE2−/−, WT mice (BMMC–>Kit−/− mice), and six weeks later were orthotopically implanted with Panc-02 cells. Tumor sizes were measured at day 28 and survival times were monitored. Pancreatic tissues were studied by immunohistochemistry and flow cytometry to analyze immunocytes. Results: A relatively high infiltration of human mast cells into the tumor microenvironment was predictive of poor patient survival (P = 0.008). An early influx of mouse mast cells and upregulation of IL-10 and receptors were consistently found in the microenvironment during PDAC development in K-rasG12V mice. By day 36, none of PDAC tumor bearing WT mice survived, 77.5% of tumor bearing Kit−/− mice survived, and 53.3% of tumor bearing BMMC–>Kit−/− mice survived (P < 0.001). There were significantly more immature neutrophils (CD45+ F4/80− CD11b+ Gr-1low) in the tumor microenvironment of WT mice than in Kit−/− mice (P < 0.001). Preliminary test showed tumor sizes were smaller in IL-10−/− BMMC–>Kit−/− mice than PGE2−/− BMMC–>Kit−/− mice (P = 0.017). Conclusions: Mast cells migrate to the tumor microenvironment and mediate the local immune suppression that promotes the growth and development of PDAC. These data suggest that targeting mast cell immunosuppressive function may be a promising novel therapy for PDAC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3822.