Abstract B034: Myeloperoxidase limits tumor-associated neutrophils mediated immunosuppression in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a survival rate under 12%. Treatments like immunotherapy and chemotherapy are ineffective in PDAC due to the immunosuppressive tumor microenvironment, in which tumor-associated neutrophils (TANs) are a major component. TAN immunosuppression has been shown to depend upon increased production of reactive oxygen species, with myeloperoxidase (MPO) being a major source of it. We investigated the contribution of MPO in mediating TAN immunosuppression using orthotopic PDAC models in wild-type and syngeneic MPO-deficient mice. We observed a significant delay in tumor growth and improved clinical scores when MPO was deficient. Additionally, treatment with the MPO-specific inhibitor Verdiperstat also delayed tumor growth. Flow cytometry analysis of the tumor microenvironment further confirmed a significant increase in CD8 T and NK cells, along with an increase in granzyme B level in both subsets, when MPO was deficient. Additionally, there was an increase in activation marker (CD25) and memory subset among both CD8 and CD4 T cells in MPO-deficient mice. Ex vivo studies with isolated TANs from tumor-bearing mice showed reduced CD8 T and NK cell suppression, and reactive oxygen species level in absence of MPO, supporting the contribution of MPO in TAN immunosuppression. These data suggest that loss of MPO in TANs has decreased immunosuppressive functions resulting in increased cytotoxic and activated T cells and NK cells with increased memory response within the tumor microenvironment. Our results demonstrate the contribution of MPO in regulating tumor progression, TAN immunosuppression, and immune cell infiltration using an orthotopic PDAC model. Citation Format: Angisha Basnet, Brain Boone, Tracy Liu. Myeloperoxidase limits tumor-associated neutrophils mediated immunosuppression in pancreatic cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84 (17 Suppl₂): Abstract nr B034.