Abstract A024: POSTPRANDIAL CHANGES TO SYSTEMIC METABOLISM IMPRINT DURABLE CHANGES ON T CELL IMMUNE RESPONSES

Abstract While nutrient availability and intrinsic metabolic pathways play key roles in T cell function and fate, systemic nutrient availability waxes and wanes with every meal. How postprandial metabolism affects T cell function and fate are unstudied. Here we show short periods of fasting and refeeding can have long-lasting effects on T cell immunity. Mouse or human T cells from fed hosts have higher mitochondrial quality and respiratory capacity than those from fasted hosts ex vivo. These metabolic phenotypes persist after activation and expansion, both in vitro culture and in vivo in response to vaccination. Fed T cells outcompete fasted T cells in a co-transfer model, such that T cells from fasted hosts form far fewer memory T cells. Serum profiling revealed triglycerides as a driver of postprandial metabolic reprogramming: chylomicrons enriched from the lymphatics of fed mice were sufficient to enhance mitochondria of fasted T cells. LDLR-deficient T cells had the metabolic phenotype of fasted T cells and were insensitive to fed serum, confirming the role of triglyceride uptake in postprandial T cell metabolic programming. Transcriptomic analysis revealed higher expression of LDLR, OXPHOS proteins, and fatty acid metabolism enzymes in fed T cells over fasted T cells. Finally, human CAR T cells manufactured from the same donor after a meal show a therapeutic advantage over T cells collected in the fasted state. In summary, postprandial metabolism imparts durable metabolic and functional advantage on T cells. Our study highlights the need to consider diet content and timing as key factors in immune cell analysis, vaccination strategies, and the generation of cellular therapies for cancer. Citation Format: Alok Kumar, Dayana B Rivadeneira, Alison Kohan, Greg Delgoffe. POSTPRANDIAL CHANGES TO SYSTEMIC METABOLISM IMPRINT DURABLE CHANGES ON T CELL IMMUNE RESPONSES [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A024.