Pancreatic ductal adenocarcinoma (PDA) is a deadly disease with a 5-year survival of only 10%. PDA is characterized by an abundant fibroinflammatory stroma that includes abundant fibroblasts and immune cells, mainly myeloid cells. Infiltrating myeloid cells express high levels of Arginase 1 (Arg1), an enzyme that metabolizes L-arginine. Conversely, CD8+ T cells are scarce in PDA, and when present have an overwhelmingly exhausted phenotype. Whether myeloid cell Arginase is a key driver of immune suppression in pancreatic cancer is unknown. Here, we tested the hypothesis that myeloid cells in the tumor microenvironment mediate immune suppression in PDA through expression of Arg1. To test this hypothesis, we used a combination of genetically engineered pancreatic cancer mouse models and pharmacological approaches. Using a FlpO- and Cre-based dual recombinase system, we have generated a mouse model that develops pancreatic cancer spontaneously because of oncogenic Kras expression in the epithelium, while at the same time lacking Arg1 expression in the myeloid cell compartment (Ptf1a-FlpO/+;KrasFrt-STOP-Frt-G12D/+;LysMCre;Arg1f/f). To complement the genetic model and inhibit the function of Arginase systemically, we used an Arginase inhibitor (CB-1158, Incyte, Inc.) alone and in combination with an immune checkpoint blockade (anti-PD1). Using these multiple approaches, we observed decrease progression to invasive disease in the genetic model, and sensitization to immune checkpoint treatment in the transplantation model. In both settings, changes in tumor growth were accompanied by an increase in CD8+ T cell infiltration and activation. These changes support the notion that myeloid Arg1 is mediator of immune suppression in PDA, and a potential therapeutic target.
Citation Format: Rosa E. Menjivar, Zeribe Nwosu, Wenting Du, Katelyn Donahue, Carlos Espinoza, Ashley Velez-Delgado, Kristee Brown, Wei Yan, Christopher Halbrook, Yaqing Zhang, Costas Lyssiotis, Marina Pasca di Magliano. Deletion of Arginase 1 in myeloid cells alters the pancreatic cancer microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-116.