Targeting epigenetic crosstalk that restrains the responses of exhausted T cells to immune checkpoint blockade therapy

Abstract Epigenetic scarring of exhausted CD8 T (TEX) cells during chronic virus infections or cancer remains a major cell-intrinsic barrier to cell immunotherapies, including immune checkpoint blockade (ICB). For successful epigenetic reprogramming TEX cells, it is crucial identify and target the molecular mechanisms underlying terminal exhaustion. Previous work revealed that de novo DNA methylation enforces silencing function restrains their responses ICB therapy. Yet, largely unknown whether post-translational histone modifications crosstalk with progression To better understand interplay between these in chronically stimulated we employed our novel vitro model human dysfunction, as well preclinical models exhaustion LCMV infection. We found significant relationship dynamic changes cells. Importantly, targeting key histone-modifying enzyme dysfunctional improved effector cytotoxicity vitro. In addition, infection, combined treatment by selective inhibitor anti-PD-L1 significantly enhanced stem-like cytolytic subsets further explored impact on programming These findings provide important mechanistic insights for developing therapeutic approaches epigenetically reprogram enhance immunotherapies. Supported Ohio State University College Medicine OSU Comprehensive Cancer Center.