Metabolic modulation unleashes immune vigor in murine pancreas tumors

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B131
Abstract ID: 5807

Presenting Author:
Maria Poimenidou , Graduate Student at Med. Col. of Wisconsin

Abstract:

Our study investigates the transformation of the pancreatic ductal adenocarcinoma tumor microenvironment from an immune-excluded to an immune-inflamed state using metabolic inhibitors metformin and mitochondria-selective conjugates, MMe and pCF₃-MMe. In murine models of pancreas cancer, MMe and pCF₃-MMe exhibited potent inhibition of tumor growth. Flow cytometry indicated increased levels of total T cells, activated CD8+, and NK T cells in MMe and pCF₃-MMe treated mice. The anti-tumor effects of these metabolic inhibitors were reversed upon CD8+ T cell immunodepletion. In vitro experiments demonstrated elevated levels of pro-inflammatory chemokines in MMe-treated tumor cells, aligned with increased CD8+ T cell infiltration. Furthermore, metabolic inhibitor treatment activated both helper CD4+ and cytolytic CD8+ T cells, with the latter demonstrating increased glycolysis and acidification rates indicative of enhanced activation. Flow cytometry corroborated these findings, revealing heightened proliferation and activation markers on treated T cells. In addition to the direct effects on T cells, immunofluorescence microscopy suggested the activation of the mitochondrial antiviral-signaling protein (MAVS) pathway in tumor cells and an increase in apoptosis as indicated by the significant increase in caspase 3/7. Our findings highlight the potential of metabolic inhibitors to activate anti-tumor immune responses directly and indirectly in murine pancreas tumors.