Abstract #LB-148: Mast cells in the tumor microenvironment are essential for the tumorigenesis of pancreatic ductal adenocarcinoma (PDAC)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Objectives: Immunocytes in the tumor microenvironment play key roles in tumorigenesis. Our previous studies using a transgenic spontaneous PDAC mouse model revealed an early influx of mast cells into the tumor microenvironment. To further assess the role of mast cells in the tumorigenesis of PDAC, we employed two complementary approaches: genetically using a mast cell deficient Kitw-sh/w-sh mouse model ( Kit mice), and pharmacologically using cromolyn, a mast cell degranulation inhibitor. Methods: Panc-02 PDAC cells were orthotopically implanted into the pancreas of Kit mice and wild type C57BL/6 mice ( WT mice). In the mast cell reconstitution model, Kit mice received intraperitoneal (IP) injections of mast cells derived from bone marrow of WT mice and six weeks later were orthotopically implanted with Panc-02 cells. In the pharmacological model, WT mice were orthotopically implanted with Panc-02 cells and were treated with daily IP injection of either cromolyn or PBS. Five mice from each group were sacrificed every seven days and tumor sizes were measured. An additional 15 mice were used for survival analysis. Pancreatic and spleen tissue were studied by immunohistochemistry and flow cytometry to analyze immunocytes, including cytotoxic T-lymphocytes (CTLs) and Th1, Th2 and Th17 phenotypes. Results : The growth of orthotopically implanted Panc-02 cells was significantly inhibited in Kit mice compared to WT mice (P = 0.033), with only 20% Kit mice having measurable tumor at day 28 (compared to 100% in WT mice). Following mast cell reconstitution of Kit mice, tumor growth was significantly increased compared to the unreconstituted Kit mice (P = 0.027). In WT mice implanted with Panc-02 cells, cromolyn treatment inhibited tumor growth and significantly improved survival compared to mice treated with PBS (P=0.025). Moreover, it was observed that Kit mice had a lower incidence of hemorrhagic ascites than WT mice (17% vs. 75%), and reconstitution of mast cells in Kit mice increased the incidence (50%) to that of WT mice. Lastly, there were significantly more Th2 and Th17 cells in the tumor microenvironment of WT mice than in Kit mice and mast cell reconstitution in Kit mice increased Th2 and Th17 cell infiltration. We also observed significantly more CTLs in the tumor microenvironment of Kit mice compared to WT mice, and mast cell reconstitution of Kit mice decreased the tumor-infiltrating CTLs to levels comparable to those of WT mice. Conclusions: Mast cells in the tumor microenvironment appear to play an essential role in promoting the tumorigenesis of PDAC. It is possible that mast cells exert this effect through the recruitment of Th2 and Th17 cells and by decreasing CTLs in the tumor microenvironment. Therefore, increasing our understanding of how mast cells act to promote tumor growth is important for the understanding of PDAC tumor biology and they may be a useful target for therapeutic intervention. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-148.