Arginase 1 is a key driver of immune suppression in pancreatic cancer

An extensive fibroinflammatory stroma rich in Macrophages is a hallmark of Pancreatic Cancer. In this disease, it is well appreciated that Macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive Macrophages are classically defined by the expression of the enzyme Arginase 1 (ARG1), which we demonstrated is potently expressed in pancreatic tumor-associated Macrophages from both human patients and mouse models. While routinely used as a polarization marker, ARG1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in Pancreatic Cancer. Genetic inactivation of Arg1 in Macrophages, using a dual recombinase genetically engineered mouse model of Pancreatic Cancer, delayed formation of invasive disease, while increasing CD8⁺ T cell infiltration. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of Macrophages. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit Arginase. Treatment of established Tumors with the Arginase inhibitor CB-1158 exhibited further increased CD8⁺ T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the Tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in Pancreatic Cancer by depleting arginine and inhibiting T cell activation.