Investigating the role of DRP1 in mediating an immune suppressive TME in KRAS mutant pancreatic cancer 2696

Abstract Description Pancreatic cancer is a devastating disease with a dismal 5-year relative survival rate of 13%. Innovative therapies that leverage the immune system to kill cancer hold great promise for treatment. However, pancreatic tumors exhibit dysregulated mitochondrial dynamics, which leads to enhanced cell growth and the development of an immune-suppressive tumor microenvironment (TME), limiting treatment efficacy. We previously demonstrated that mutated Kras, the most common mutation in pancreatic cancer, led to increased activation of DRP1, leading to increased mitochondrial fission, elevated glycolysis, and greater lactate secretion. Yet, the full impact of DRP1 expression on the pancreatic TME remains unclear. We hypothesize that activation of the DRP1 pathway is sufficient to generate an immune-suppressive TME. Knocking out DRP1 in patient-derived cell lines revealed an altered cytokine secretion profile, reduced lactate secretion, and slower tumor growth in vitro and in vivo. DRP1 KO cells exhibited increased IL-6 secretion, and immunohistochemical staining of DRP1 KO tumors demonstrated increased T cell infiltration compared with DRP1-expressing controls. Implications for suppressive fibroblast and myeloid cell recruitment and differentiation will be discussed. A greater understanding of the role of DRP1 in pancreatic cancer may lead to insights regarding oncogene-driven metabolic changes in tumor cells and opportunities for therapeutic targeting. Funding Sources T32CA009109-48 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)