Abstract 926: Myeloperoxidase limits tumor-associated neutrophils mediated immunosuppression in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a survival rate under 13%. 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. The immunosuppressive function of TANs has been shown to depend upon increased production of reactive oxygen species, with myeloperoxidase being a major source of it. We investigated the contribution of myeloperoxidase in mediating tumor-associated neutrophils immunosuppression using orthotopic PDAC models in wild-type and syngeneic myeloperoxidase-deficient mice. We observed a significant delay in tumor growth and improved clinical scores when myeloperoxidase was deficient. Additionally, treatment with the myeloperoxidase-specific inhibitor verdiperstat delayed tumor growth. Flow cytometry analysis of the tumor microenvironment revealed a significant increase in CD8+ T cells and natural killer (NK) cells in MPO-deficient mice, accompanied by elevated granzyme B levels in both cell subsets. Additionally, MPO deficiency was associated with increased expression of activation and memory markers among both CD8+ and CD4+ T cells. Ex vivo studies with isolated TANs from tumor-bearing mice showed reduced CD8+ T cell and NK cell suppression, and reactive oxygen species level in the absence of myeloperoxidase. These data suggests that loss of myeloperoxidase in TANs results in decreased immunosuppressive functions and increased cytotoxic and activated T cells and NK cells within the tumor microenvironment. Depletion of NK cells in myeloperoxidase-deficient mice abolished the antitumor effects observed with myeloperoxidase loss, underscoring the critical role of NK cells as key mediators of the antitumor response in the absence of myeloperoxidase. Additionally, we observed an enhanced chemotherapy (Gemcitabine) and immunotherapy (anti-PD1 and ant-CTLA4) response with myeloperoxidase deficiency. Overall, our results demonstrate the contribution of myeloperoxidase in regulating PDAC tumor progression, TAN immunosuppression, treatment response and immune cell infiltration using an orthotopic PDAC model. Citation Format: Angisha Basnet, Kaitlyn M. Landreth, Tracy W. Liu. Myeloperoxidase limits tumor-associated neutrophils mediated immunosuppression in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 926.