DE NOVO EPIGENETIC PROGRAMS INHIBIT PD-1 BLOCKADE-MEDIATED T-CELL REJUVENATION
By Hazem E. Ghoneim, Yiping Fan, A. Moustaki, Hossam A. Abdelsamed, P. Dash, P. Dogra, Robert A. Carter, Walid Awad, G. Neale, P. Thomas and 1 more. Cell, 2017
697 citations recorded by the source corpus.
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.
Subfields: Immunology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/b0cf82934a2c0327202f54786ec7e7d77e4aff26
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In Immunology
- Ton N. Schumacher
- J. Wolchok
- D. Thommen
- Laura M. McLane
- Mohamed S. Abdel-Hakeem
- E. Wherry
- Rafi Ahmed
- A. Schietinger
In Molecular Biology
Citations in the corpus
- The future of cancer immunotherapy: microenvironment-targeting combinations (2020, background): “Reinvigoration of exhausted T cells by ICI is associated with significant chromatin remodeling, suggesting that epigenetic manipulation may benefit some patients with exhausted T cell function.(76) HDAC inhibitors inhibit activation-induced cell death (AICD) of T cells, and preclinical models indica”
- T Cell Dysfunction in Cancer (2018, background): “In addition to the sustained demethylation of PDCD1, dysfunctional T cells also progressively acquire de novo methylation of genes associated with effector functions during both infections and tumor development, which could not be reverted by PD-1 blockade (Ghoneim et al., 2017).”
- CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “(281) found a key role for Dnmt3a-dependent events in limiting PD-1 blockade–mediated reinvigoration.”