Abstract A31: Investigating the effect of myeloid Arg1 deletion on tumor growth and CD8+ T-cell infiltration and activation in pancreatic cancer

Abstract

Abstract PDA is characterized by an extensive fibroinflammatory stroma. This fibroinflammatory stroma is mainly composed of fibroblasts and tumor-infiltrating immune cells. The most abundant infiltrating immune cells are myeloid cells. Myeloid cells including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells, and granulocytes are required for PDA tumor growth and maintenance. Myeloid cells have the ability to suppress antitumor T-cell responses in PDA, as depletion of myeloid cells restores CD8+ T-cell immunity. Our previous characterization of myeloid cells infiltrating the neoplastic pancreas has revealed that myeloid cells express high levels of Arginase 1 (Arg1), an enzyme that depletes the amino acid L-arginine from the microenvironment and a signature marker of immunosuppressive macrophages and TAMs. In turn, L-arginine is required for CD8+ T-cell activation. An increase in Arginase levels has been reported also in other cancers, including lung, gastrointestinal, and bladder cancer. Thus, Arg1 expression in myeloid cells might be a key mediator of immune suppression, although this possibility has not been investigated directly in pancreatic cancer. Based on these observations, we test the hypothesis that myeloid cell polarization in the tumor microenvironment mediates immune suppression in PDA through expression of Arginase 1. The objective of this study is to provide novel insights into the role of Arg1 in pancreatic cancer, and the overall goal is to identify new therapeutic targets for combination therapy in pancreatic cancer. We used a genetically engineered mouse model (LysM-Cre;Arg1f/f) to delete the Arg1 gene, specifically from the myeloid cell compartment (LysM+ cells), including macrophages and neutrophils. We orthotopically implanted primary mouse pancreatic cancer cell lines into C57BL/6 LysM-Cre;Arg1f/f and wild-type (WT) mice. We evaluated tumor growth and CD8+ T-cell infiltration and activation between LysM-Cre;Arg1f/f and WT control mice. We used MRI imaging to determine tumor volume, and we used immunofluorescence and mass cytometry analysis to investigate changes in immune cell infiltration. We confirmed Arg1 depletion in LysM-Cre;Arg1f/f mice by Western blotting, co-immunofluorescence, and mass cytometry. We observed a decreasing trend in tumor growth and volume in LysM-Cre;Arg1f/f mice, an increase in iNOS expression (a marker of inflammatory macrophages), and an increase in CD8+ T-cell number and activity compared to the WT. These results support the notion that Arg1 might be a moderator of immune suppression in pancreatic cancer. Citation Format: Rosa E. Menjivar, Christopher Halbrook, Ashley Velez, Fatima Lima, Carlos Espinoza, Stefanie Galban, Yaqing Zhang, Costas Lyssiotis, Marina Pasca di Magliano. Investigating the effect of myeloid Arg1 deletion on tumor growth and CD8+ T-cell infiltration and activation in pancreatic cancer [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 A31.