Histone demethylases KDM5A/B regulate epigenetic programming of exhausted T cells and restrain immunotherapy responses 4207

Abstract Description Epigenetic silencing of effector and stemness genes in exhausted CD8 T cells (TEX) poses a considerable hurdle to effective T cell immunotherapies. While de novo DNA methylation is known to enforce T cell exhaustion, the role of histone modifications in shaping these methylation patterns remains unclear. Notably, H3K4me3 marks, which hinder Dnmt3a-mediated de novo DNA methylation, are enriched at effector/memory-associated genes in the cytolytic subset of TEX cells but are lost in terminally exhausted cells. Through integrated epigenetic profiling in both our in vitro model of human T cell dysfunction and a preclinical model of exhaustion, we observed characteristic patterns of H3K4me1/3 modifications and DNA methylation that distinctly map to different TEX subsets. Importantly, our findings demonstrate that therapeutic inhibition or genetic targeting of the H3K4 demethylases KDM5A/KDM5B enhanced effector function and cytotoxicity in dysfunctional human CD8 T cells. Furthermore, combined KDM5A/B blockade with anti-PD-L1 therapy expanded both progenitor and cytolytic TEX populations during chronic LCMV infection or cancer. These findings reveal a novel epigenetic histone-DNA methylation axis underlying terminal exhaustion and identify H3K4 demethylases as potential therapeutic targets for enhancing immunotherapy efficacy. Funding Sources Supported by NIH R01AI170926; NIH T32AI165391; Ohio State College of Medicine/Comprehensive Cancer Center funding Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)