Paper

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

Halbrook, Christopher J., Kadiyala, Padma, Salas-Escabillas, Daniel, Menjivar, Rosa E., Velez-Delgado, Ashley, Espinoza, Carlos, Lima, Fatima, Carpenter, Eileen, Lyssiotis, Costas A., Pasca di Magliano, Marina, Bednar, Filip, Brown, Kristee, Yan, Wei, Crawford, Howard, Zhang, Yaqing, Nwosu, Zeribe C., Donahue, Katelyn L., Du, Wenting, Bischoff, Allison

2022

Overview

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 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. 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. Thus, our data demonstrate that Arg1 is more than simply a marker of macrophage function. Rather, Arg1 is also a driver of immune suppression and represents a promising immunotherapeutic target for pancreatic cancer.

• Publisher: Cold Spring Harbor Laboratory
• Subject: Cancer Biology