Abstract 5119: Serine proteases modulate neutrophil survival and contribute to immunosuppression

Abstract Tumor-promoting inflammation is a hallmark of cancer, contributing to malignant cells’ survival and proliferation. Infiltrating leukocytes and pro-inflammatory cytokines released into the tumor microenvironment (TME) often cause this inflammation. We have previously shown that increased infiltrating neutrophils are associated with pancreatic ductal adenocarcinoma (PDAC) disease progression, which correlates with increased inflammation and neutrophil accumulation. Prolonged neutrophil accumulation has been linked to chronic inflammation, which in turn is thought to contribute to tumor progression, therapy resistance, and metastasis. In the present study, we examined how neutrophil-PDAC interaction enhances the survival of neutrophils dependent on serine proteases and their inhibitors. Previous reports suggest that serine proteases, such as cathepsin G, can contribute to inflammation and induce caspase-independent neutrophil apoptosis. We examined the role of serine proteases and their inhibitors on neutrophil survival using defined cellular models. We observed an association between increased serine protease and neutrophil survival. Moreover, this survival was modulated by cellular aggressiveness and therapy resistance. In addition, we observed increased survival of neutrophils associated with inhibition of serine proteases and increased expression of serpins to proteases in neutrophils upon PDAC cancer cell conditioned media treatment. In summary, these studies point to neutrophil serine proteases and their inhibitors as versatile mediators that modulate neutrophil survival, leading to an immunosuppressive microenvironment and identifying them as potential targets for therapeutic interventions. Citation Format: Reegan Sturgeon, Sumanas Maram, Ainsley Meyerson, Ridhi Bhola, Esther Johnson, Rakesh K. Singh. Serine proteases modulate neutrophil survival and contribute to immunosuppression [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 5119.