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De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation
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.
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“In antigen-stimulated mouse CD8 + T cells and human chimeric antigen receptor (CAR) T cells, deficiency in DNMT3A or TET2 is associated with normal primary immune responses but enhanced secondary responses with increased memory precursor and central memory T cell differentiation 163-166,183,187 .”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [164]
In the citing paper
“While TET2 deficiency does not result in significant methylation changes at the Eomes locus 163 , DNMT3A deficiency leads to a reduction in Tcf7 promoter methylation, consistent with DNMT3A localization to the Tcf7 promoter in DNMT3A wild-type T cells164.”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [164]
In the citing paper
“These phenotypic changes correlate with increased expression of the master transcription factors TCF1 (encoded by Tcf7) or EOMES in absence of DNMT3A or TET2, respectively[164][165][166]183,187.”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [164]
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Metadata
- Authors
- Ghoneim, H. E., Fan, Y., Moustaki, A., Abdelsamed, H. A., Dash, P., Dogra, P., Carter, R., Awad, W., Neale, G., Thomas, P. G., & Youngblood, B.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 170
- Issue
- 1
- Pages
- 142-157.e19
- ISSN
- 0092-8674
- Cited by
- 781
- References
- 40
- Language
- en
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 393 d)
- Funders
- National Institutes of Health (1R01AI114442)
- ALSAC
- SJCRH Garwood Postdoctoral Fellowship
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