Howard lazarus austin resume ann arbor11/23/2023 Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting arginine and inhibiting T cell activation. 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. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit arginase. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of macrophages. 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. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. While routinely used as a polarization marker, ARG1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. 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. 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. Chao Family Comprehensive Cancer Center, University of California, Irvine, United States Īn extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer.Department of Molecular Biology and Biochemistry, University of California, Irvine, United States.Department of Internal Medicine, Division of Gastroenterolog, University of Michigan-Ann Arbor, United States.Henry Ford Pancreatic Cancer Center, United States.Department of Cell and Developmental Biology, University of Michigan-Ann Arbor, United States.Department of Immunology, University of Michigan-Ann Arbor, United States.Cancer Biology Program, University of Michigan-Ann Arbor, United States.Department of Surgery, University of Michigan-Ann Arbor, United States.Department of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, United States.Cellular and Molecular Biology Program, University of Michigan-Ann Arbor, United States.
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