VDAC oligomerization in T-cells: the role of oxidative stress in immune response 4616

Description T-cell metabolic fitness is crucial for their effectiveness in tumor immunotherapy, influencing proliferation, survival, and function. Enhancing mitochondrial performance is a promising strategy to improve therapeutic outcomes. Voltage-dependent anion channels (VDACs) in the mitochondrial outer membrane regulate energy metabolism, apoptosis, and calcium homeostasis. We hypothesized that VDAC oligomerization, particularly under oxidative stress, significantly impacts T-cell states, thereby presenting opportunities for intervention. We investigated modulating VDAC oxidation through small molecules and genetic approaches using mouse T cells and human PBMCs. Novel inhibitors targeting VDAC oxidation and genetic models with VDAC1 mutations were developed. Vdac-1-deficient T cells exhibited enhanced expansion and a central memory phenotype. Pharmacological and genetic VDAC1 inhibition promoted memory-like subsets with increased memory-associated gene expression and fewer exhaustion markers. In human T cells, VDAC oxidation inhibition reduced exhaustion. Mice expressing the VDAC1C127A mutation exhibited lower oxidative stress and fewer exhausted T cells, highlighting the importance of this residue in regulating T-cell fitness. These findings underscore VDAC proteins as key oxidative stress regulators and suggest targeting VDAC oxidation as a novel strategy to enhance T-cell efficacy in tumor immunotherapy. Funding Sources This study was funded by the Intramural NIH funds.