Abstract PO-019: The JAK/STAT3 pathway drives myeloid-mediated immunosuppression in pancreatic cancer

Pancreatic Ductal Adenocarcinoma (PDAC) is a lethal malignancy with a 5-year survival rate of 10%. PDAC is characterized by a dense stroma with a heterogeneous population of fibroblasts and infiltrating immune cells. While the immune infiltration is abundant, it is mostly composed of immunosuppressive cells, such as tumor associated macrophages and myeloid derived suppressive cells (MDSCs). Hence, effective anti-tumor CD8+ T cell responses are not elicited in PDAC. My preliminary data shows that the JAK/STAT3 signaling pathway is active in the stroma, specifically in fibroblasts and myeloid cells. My main goal is to investigate the role of JAK/STAT3 signaling pathway in driving immunosuppression by myeloid cells. I hypothesize that targeting JAK/STAT3 pathway in myeloid cells will lead to reversion of the immunosuppressive phenotype aiding in the treatment of pancreatic cancer. To understand the role of JAK/STAT3 signaling in the polarization of myeloid cells and consequently in tumor growth, I used a genetically engineered mouse model (LysMCre;Stat3f/f) that depletes Stat3 specifically in myeloid cells. Using this mouse model, I implanted syngeneic tumor cells orthotopically in the pancreas. After two weeks, I weighed the tumor, and assessed the immune infiltration by Mass Cytometry (CyTOF). Deleting Stat3 from myeloid cells resulted in a significant decrease in tumor mass compared to controls. Analysis showed a decrease in macrophages and increase in memory CD8+ and CD4+ T cells, suggesting a decrease in the immunosuppressive capacity of the myeloid cells. Currently, I am investigating the mechanism by which JAK/STAT3 pathway disruption impairs tumor growth. Citation Format: Ashley Velez-Delgado, Kristee Brown, Marina Pasca di Magliano. The JAK/STAT3 pathway drives myeloid-mediated immunosuppression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-019.