Abstract A54: Oncogenic Kras modulates pancreas plasticity and the tumor microenvironment

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) has an exceedingly poor prognosis, with only 9% 5-year survival rate. Kras mutations are found in 90% of cases of pancreatic cancer and drive the formation of pancreatic intraepithelial neoplasia (PanIN), precursor lesions to PDA. Both PanIN and PDA are characterized by dense stroma, containing fibroblasts and immune cells. The infiltrating immune cells have a suppressive phenotype and prevent antitumor immunity by cytotoxic T cells. The mechanisms underlying the immunosuppression in pancreatic cancer are only partially understood. Our goal is to investigate the interactions between tumor cells and the immune cells, with the long-term objective to identify new therapeutic targets. Our laboratory has described a mouse model (iKras*) of inducible and reversible expression of oncogenic Kras (Kras*) in the pancreas. Taking advantage of the reversibility of Kras* expression in this model, we conducted a thorough characterization of the immune infiltration and function upon modulation of Kras* at different stages of pancreatic carcinogenesis. iKras* mice and wild-type littermates were enrolled in experiments at the age of 8-12 weeks. Kras* expression was activated, then we induced acute pancreatitis to promote the formation of preneoplastic lesions. After 3 weeks, a time when widespread low-grade lesions and fibrosis are observed, mice were either harvested or Kras* expression was inactivated and 3 days or 1 week later the pancreas was harvested. We performed flow cytometry, immunohistochemistry, and CyTOF in the pancreas to analyze T cell and myeloid cell populations, as well as functional markers (Arg1, iNOS, IFNγ). Myeloid cells and T cells infiltrated the pancreas in presence of active Kras*. Inactivation of Kras* resulted in a relatively modest decrease in infiltrating myeloid cells and a modest increase in CD4+ T cells, particularly regulatory T cells. However, analysis of the functional marker Arg1, a putative immune suppressive molecule expressed in myeloid cells, indicated that its expression depends on Kras*-expressing cells. Kras* in the neoplastic cells initiates the infiltration of immune cells into the pancreas and induces them to express immune-suppressive factors. Going forward, we are investigating the signals downstream of oncogenic Kras that mediate the crosstalk between neoplastic cells and infiltrating immune cells. Citation Format: Ashley Velez-Delgado, Valerie Irizarry-Negron, Rosa Menjivar, Jenny Lazarus, Murali Bollampally, Nina Steele, Timothy Frankel, Fillip Bednar, Yaqing Zhang, Marina Pasca di Magliano. Oncogenic Kras modulates pancreas plasticity and the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A54.