Abstract B015: Targeting myeloperoxidase delays pancreatic cancer growth and enhances chemotherapy response

Abstract

Pancreatic cancer remains one of the deadliest diseases, with fewer than 13% of patients surviving beyond 5 years after diagnosis. Its resistance to current therapies is driven in part by a uniquely immunosuppressive tumor microenvironment, primarily characterized by an extensive infiltration of tumor-associated myeloid cells. These innate immune cells are strongly associated with poor prognosis and diminished therapeutic outcomes in pancreatic cancer patients. Reactive oxygen species (ROS) produced by tumor-associated myeloid cells contribute to immune suppression and treatment resistance, with myeloperoxidase (MPO), a myeloid lineage-restricted enzyme, serving as a major source of ROS. Our data demonstrate that MPO expression is elevated in pancreatic cancer compared to normal tissue and that MPO rich tumor microenvironments are associated with poor clinical outcomes by imaging mass cytometry. Additionally, increased MPO activity is observed in blood-isolated neutrophils from patients with late stage pancreatic cancer and in chemotherapy resistant patients compared to responders. Our preclinical studies demonstrate that both genetic deletion and pharmacologic inhibition of MPO significantly delayed pancreatic tumor growth and prolong survival through NK cell and T cell dependent mechanisms. MPO targeting remodeled the tumor microenvironment by increasing T cell, NK cell, and Ly6G+ myeloid cell infiltration while reducing collagen deposition. Mechanistically, Ly6G+ myeloid cells isolated from MPO-deficient or inhibitor-treated tumor-bearing mice exhibited reduced ROS production, neutrophil extracellular trap formation, immunosuppressive ccheytokine secretion, T cell suppression, and immunosuppressive, pro-tumor transcriptional programs. Consistent with enhanced antitumor immunity, depletion of NK or T cells abolished the therapeutic benefit of targeting MPO. Furthermore, MPO deficiency and inhibition sensitized tumors to gemcitabine, demonstrating synergy with standard of care chemotherapy. Collectively, these findings identify MPO as a clinically relevant therapeutic target that remodels the immunosuppressive tumor microenvironment, enhances antitumor immunity, and overcomes chemoresistance.