Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
- PMID: 27789795
- PMCID: PMC5484795
- DOI: 10.1126/science.aaf2807
Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
Abstract
Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.
Copyright © 2016, American Association for the Advancement of Science.
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Comment in
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Can T cells be too exhausted to fight back?Science. 2016 Dec 2;354(6316):1104-1105. doi: 10.1126/science.aal3204. Science. 2016. PMID: 27934723 No abstract available.
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Immunology: The chronicles of T-cell exhaustion.Nature. 2017 Mar 9;543(7644):190-191. doi: 10.1038/nature21508. Epub 2017 Feb 22. Nature. 2017. PMID: 28225757 No abstract available.
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Epigenetic Remodeling in Exhausted T Cells: Implications for Transplantation Tolerance.Transplantation. 2017 May;101(5):894-895. doi: 10.1097/TP.0000000000001720. Transplantation. 2017. PMID: 28437384 Free PMC article. No abstract available.
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