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

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