Abstract PR05: Dgat1 camouflages sexual dimorphism in anti-tumor CD8+ T cell immunity

Abstract The tumor microenvironment (TME) is enriched in various lipid species that are detrimental to anti-tumor T cell function. However, intratumoral CD8+ T cells were recently shown to require free fatty acids, which are also abundant in the TME, for survival and function. It is not clear whether these free fatty acids regulate transcription or serve as an energy source either directly or through a triacylglyerol (TAG) intermediate step (as in memory CD8+ T cells). Here, we generated mice with T cell-specific deletion of Dgat1, the enzyme that catalyzes the last and rate limiting step in TAG synthesis. We found that the function of Dgat1 in melanoma-infiltrating CD8+ T cells is sexually dimorphic. In female mice, loss of Dgat1 results in much smaller tumors whereas in male mice Dgat1 deficiency limits anti-tumor T cell function. Mechanistically, Dgat1 is required for the survival of stem-cell like Tim3-Slamf6+CD8+ T cells in male mice, but actively decreases their abundance in female mice in a CD8+ T cell-intrinsic manner. Using a number of mouse models we reveal that androgen receptor signaling induces the accumulation of lipid peroxides and the activation of the unfolded protein response in Dgat1-deficient CD8+ T cells. Our study provides insights into a previously unexplored metabolic adaptation of tumor-infiltrating T cells to sex hormones. Citation Format: Alaa Madi, Guoliang Cui. Dgat1 camouflages sexual dimorphism in anti-tumor CD8+ T cell immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr PR05.