Abstract A078: Choline metabolism promotes the immunosuppressive function of pancreatic tumor macrophages

Abstract Macrophages contribute to immunosuppression and tumor progression in the pancreatic tumor microenvironment. Recent studies highlight the role of metabolic reprogramming in regulating macrophage function. Targeting altered metabolism in PDAC macrophages is a potential strategy to modulate their function and inhibit tumor progression. We characterized the metabolic state of tumor macrophages in a subcutaneous PDAC mouse model using liquid chromatography-mass spectrometry (LCMS) based untargeted metabolomics. We identified glycerophosphocholine (GPC), an intermediate in choline metabolism, as significantly elevated in PDAC macrophages. To further investigate the role of choline metabolism in regulating PDAC macrophage function, we used an in vitro macrophage model supplemented with PDAC tumor conditioned media (CM). Metabolomics analysis revealed elevated choline metabolites in the tumor CM supplemented macrophages. Using stable isotope labelled choline tracing, we show an increased fractional contribution of media choline to downstream choline metabolites including GPC. Using qPCR and flow cytometry, we show that Inhibiting choline metabolism using choline kinase inhibitors increased the expression of pro-inflammatory M1 macrophage markers and decreased anti-inflammatory M2 markers. This suggests a novel role for choline metabolism in promoting the anti-inflammatory state in PDAC macrophages. In vivo injection of a choline kinase inhibitor reduced tumor growth in mice bearing subcutaneous PDAC tumors. Our findings suggest that targeting choline metabolism in PDAC macrophages may offer a promising strategy to regulate their immunosuppressive function and inhibit pancreatic tumor progression. Citation Format: Vineeth Vengayil, Joseph A. Tandurella, Kelsey M. Nemec, Mariko L. Bennett, F. Chris . Bennett, Clementina Mesaros, Caroline R. Bartman. Choline metabolism promotes the immunosuppressive function of pancreatic tumor macrophages [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A078.