[PDF][PDF] De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation

HE Ghoneim, Y Fan, A Moustaki, HA Abdelsamed… - Cell, 2017 - cell.com
HE Ghoneim, Y Fan, A Moustaki, HA Abdelsamed, P Dash, P Dogra, R Carter, W Awad…
Cell, 2017cell.com
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 …
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.
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