Abstract 3655: Mast cells promote immunosuppression and pancreatic ductal adenocarcinoma development
Authors: Ma Ying , Wang Huamin , Ji Baoan , Liu Yan , Deng Defeng , Abbruzzese James L. , Hwu Patrick , Logsdon Craig , Ullrich Stephen E. 
Published: June 2012

Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a mostly uniformly lethal disease and is notoriously resistant to most therapies. Immunotherapy may be a fourth strategy for treating PDAC, supplementing surgery, chemotherapy, and radiation therapy. Immunosuppression is one of the largest bottlenecks in cancer immunotherapy development. In our preliminary studies, we analyzed a panel of immunocytes in human PDAC tissue samples and found that mast cells infiltrated at the tumor margin. This high infiltration of human mast cells into the tumor microenvironment was associated with poor survival. An early influx of mast cells into the tumor microenvironment combined with the IL-10 and receptor upregulation we found in a transgenic spontaneous PDAC mouse model, was associated with malignant progression. In addition, mast cells were found to be essential to PDAC tumorigenesis in a mast cell-deficient Kitw-sh/w-sh mouse model (Kit-/- mice) compared to wild-type C57BL/6 control mice (WT mice). However, how mast cells regulate immunologic effects in the tumor microenvironment and contribute to PDAC tumorigenesis are unknown. We hypothesized that mast cells mediate the immunosuppression that promotes PDAC development.

Methods: We quantified mast cells in 16 normal human pancreas and 22 pancreatitis patients’ tissue samples. Panc-02 PDAC cells were orthotopically implanted into the pancreases of Kit-/-, mast cell-reconstituted, and WT mice. In the mast cell reconstitution model, Kit-/- mice received bone marrow-derived mast cells (BMMCs) from IL-10-/-, PGE2-/-, and WT mice. To determine whether targeting mast cells has a therapeutic effect in PDAC, we treated mice PDAC with cromolyn, a mast cell stabilizer. Saline and gemcitabine were used as controls. Tumor sizes were measured by bioluminescence imaging.

Results: Mast cell infiltration to human pancreatic disease was associated with inflammation and malignancy progression in PDAC (P&lt;0.0001), which was consistent with our previous observation in the spontaneous PDAC mouse model. The growth of orthotopically implanted PDAC tumor was significantly depressed in mice reconstituted with IL-10-/- BMMCs compared with that in Kit-/- mice reconstituted with normal BMMCs (P = 0.025). Most PDAC tumors that developed in Kit-/- mice reconstituted with IL-10-/- BMMCs were limited to the pancreas, with little peritoneal involvement. No tumors were visible in the pancreas after we treated tumor-bearing mice with cromolyn, which was more effective at eliminating tumors than was low-dose gemcitabine (P &lt; 0.001).

Conclusions: Mast cells promote inflammatory progression and immune suppression in PDAC tumorigenesis. Mast cell-targeted therapy resulted in a higher treatment response rate in mouse PDAC than did classic chemotherapy. Therefore, therapy targeting on mast cells may overcome immune suppression and improve PDAC immunotherapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3655. doi:10.1158/1538-7445.AM2011-3655