It is becoming increasingly clear that stromal responses elicited by early-stage neoplastic lesions can promote tumor progression towards a more invasive and potentially metastatic state. However, the molecular mechanisms that underlie the early recruitment of stroma, and in particular immune cells, to sites of neoplasia remain poorly understood. To address this question in the context of pancreatic adenocarcinoma, we make use of orthotopic pancreatic grafts of primary murine pancreatic ductal epithelial cells (PDEC) harboring oncogenic KRas (KRasG12D). We find that engrafted KRasG12D-expressing PDEC can elicit a significant immunological response. The nature and composition of immune infiltrates was assessed using FACS sorting as well as immunohistochemical techniques and was directly compared to those derived from p48Cre;LSL-KRasG12D mice. Our observations to date indicate that the expression of KRasG12D promotes the recruitment of immunosuppressive leukocytes in the absence of a notable increase in the cytotoxic T cell population. These results support the hypothesis that effective tumor immunity mediated by an adaptive T cell response is actively suppressed at the very early stage of pancreatic neoplasia. We are currently investigating the molecular mechanisms by which oncogenic KRas modulates the intratumoral immune response.
Citation Format: Yuliya Pylayeva-Gupta, Kyoung Eun Lee, George Miller, Dafna Bar-Sagi. KRas-mediated modulation of the immune response in pancreatic neoplasia. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A66.