Differential mitochondrial function drives sex differences in T cell exhaustion 3782

Abstract Description Recently, we and others reported that sex differences in T cell exhaustion play a critical role in driving sex disparity in anti-tumor immunity and survival outcomes. Male T cells in tumors exhibit more severe functional exhaustion than female T cells, with underlying molecular mechanisms remaining unclear. While mitochondrial function is critical for proper T cell activation and function, it remains unexplored whether sex differences in mitochondria contribute to these functional differences in male and female exhausted T (Tex) cells. Using in vitro and in vivo glioblastoma (GBM) models, we found male Tex cells exhibit greater mitochondrial mass and membrane potential but more dysfunctional mitochondria and higher ROS production, accompanied by increased Nox1 expression. Additionally, male Tex cells show enhanced mitophagy, likely compensating for increased mitochondrial damage. Treatment with antioxidant (N-acetylcysteine) or mitophagy inducer (nicotinamide riboside) mitigated the sex differences in exhausted phenotype in T cells, suggesting that differences in mitochondria function may be a driver of sex differences in T cell exhaustion. Furthermore, combining anti-PD1 and 4-1BB agonist antibodies, which enhance mitochondrial function in T cells, improved survival of both male and female pre-clinical GBM models. These findings suggest that differential mitochondrial dysfunction drives sex differences in T cell exhaustion, offering a target for sex-specific therapies. Funding Sources American Brain Tumor Association; Cleveland Clinic Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)