Cell
Volume 170, Issue 1, 29 June 2017, Pages 142-157.e19
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Article
De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation

https://doi.org/10.1016/j.cell.2017.06.007Get rights and content
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Highlights

  • Post-effector de novo DNA methylation programs promote terminal T cell exhaustion

  • Exhaustion-associated DNA methylation programs are preserved during PD-1 blockade

  • Blocking de novo methylation enhances PD-1 blockade-mediated T cell rejuvenation

  • PD-1hi TILs acquire exhaustion-associated DNA-methylation programs

Summary

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
exhaustion
epigenetic modifications
DNA methylation
tumor
DNA-demethylating agents
immune-checkpoint blockade

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