Abstract PO-052: Determining the role of Apolipoprotein E in pancreatic cancer immune suppression

Abstract

Abstract Pancreatic cancer (PDA) is a lethal malignancy with a 5-year survival rate of about 10%. The poor prognosis is, in part, due to patients most often presenting with already metastatic disease. PDA is characterized by an abundant, fibroinflammatory stroma, that contains abundant cancer-associated fibroblasts and infiltrating immune cells. Myeloid cells such as tumor-associated macrophages (TAMs) are abundant within the stroma and a key driver of immunosuppression. We and others have identified elevated expression of Apolipoprotein E (ApoE) in a subset of TAMs. Further, using single cell sequencing of human tumor samples as well as mouse tumors, we determined that ApoE expression is elevated in tumor macrophages compared to macrophages in the normal pancreas. ApoE has been well studied in various biological processes, but its role in pancreatic cancer has not been determined. In this study, we sought to determine whether ApoE had a functional role within the pancreatic cancer microenvironment. Based on observations in other systems, we hypothesized that it might be a mediator of immune suppression in pancreatic cancer. We thus implanted mouse pancreatic cancer cell lines in syngeneic wild type C57/BL6 mice or in ApoE-/- mice. We did not observe a change in tumor growth in ApoE-/- mice compared to control. However, histological and Mass Cytometry (CyTOF) analysis revealed changes in the tumor microenvironment in ApoE-/- mice. Tumors from ApoE-/- mice had fewer aSMA+ fibroblasts, and subsequently less collagen deposition. In addition, CyTOF analysis revealed an increase in CD8+ T cell and CD4+ T cell infiltration, along with a decrease in regulatory T cells. Tumors harvested from ApoE-/- mice had lower levels of both Tgfb1 and Cxcl1. Further analysis in vitro, revealed ApoE secreted from tumor-associated macrophages regulates tumor-cell derived Tgfb1 and Cxcl1. Cxcl1 in turns inhibits T cell infiltration in tumors. We are currently conducting mechanistic studies to determine the mediators of the cytokine-regulatory effects of ApoE in cancer cells. Further, we are exploring whether ApoE loss sensitizes tumors in vivo to immunoregulatory agents. Citation Format: Samantha B. Kemp, Nina G. Steele, Fatima Lima, Carlos Espinoza, Yaqing Zhang, Zeribe Nwosu, Eileen S. Carpenter, Meggie Hoffman, Amanda Pacheco, Ashley Velez-Delgado, Stephanie The, Howard C. Crawford, Marina Pasca di Magliano. Determining the role of Apolipoprotein E in pancreatic cancer immune suppression [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-052.