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

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

Author information

1
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
3
Hartwell Center for Bioinformatics & Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
4
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: benjamin.youngblood@stjude.org.

Abstract

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

PMID:
28648661
PMCID:
PMC5568784
DOI:
10.1016/j.cell.2017.06.007
[Indexed for MEDLINE]
Free PMC Article

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