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

Cell. 2017 Jun 29;170(1):142-157.e19. doi: 10.1016/j.cell.2017.06.007. Epub 2017 Jun 22.


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

Keywords: CD8 T cells; DNA methylation; DNA-demethylating agents; epigenetic modifications; exhaustion; immune-checkpoint blockade; tumor.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Animals
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology
  • DNA Methylation
  • Epigenesis, Genetic*
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Prostatic Neoplasms / drug therapy
  • Virus Diseases / drug therapy


  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor