Modulating immunometabolism in pancreas cancer 3322

Description Pancreas cancer is one of the most aggressive human malignancies. Accumulating evidence has indicated metabolic reprogramming as a necessity for pancreas cancer growth, invasion, and chemotherapeutic resistance. We investigated the antitumor and immunomodulating effects of mitochondria-targeted Metformin, MMe, in human and mouse pancreas cancer cell lines. MMe treatment in vitro induced extensive cytoplasmic vacuolization and mitochondrial swelling, and significantly reduced mitochondrial membrane potential. RNA sequencing, qPCR, and immunoblot analysis of cells treated with MMe indicated upregulated ER stress genes and increased unfolded protein response-related proteins XBP1, peIF2a, and ATF4. In line with these findings, MMe treatment inhibited cell proliferation and induced caspase-3/7-linked apoptosis. Moreover, MMe unexpectedly stimulated the oligomerization of MAVS, a key IFN-β promoter, and the downstream production of inflammatory cytokines. Finally, MMe suppressed tumor growth by 4-fold relative to the control and enhanced levels of tumor-infiltrating T cells in vivo, suggesting a potential role in altering tumor-immune crosstalk. Collectively, these data suggest that MMe has complementary tumor intrinsic and tumor extrinsic properties as an immunometabolism modifier capable of remodeling the pancreas cancer microenvironment. This dual functionality of MMe can provide a foundation for current immunotherapies by enhancing antitumor efficacy and immune activation. Funding Sources Supported by the Medical College of Wisconsin Cancer Center Fellowship. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)