De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation

Abstract

Immune-checkpoint-blockade (ICB)-mediated rejuvenation of exhausted Tcells has emerged as a promising approach for treating various cancers and chronic infections. However, Tcells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. We report that blocking de novo DNA methylation in activated CD8 Tcells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 Tcells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict Tcell expansion and clonal diversity during PD-1 blockade treatment. Moreover, these exhaustion-associated DNA-methylation programs were acquired in tumor-infiltrating PD-1hi CD8 Tcells, and approaches to reverse these programs improved Tcell responses and tumor control during ICB. These data establish de novo DNA-methylation programming as a regulator of Tcell exhaustion and barrier of ICB-mediated Tcell rejuvenation.