Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
Top Cited Papers
- 2 December 2016
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 354 (6316), 1160-1165
- https://doi.org/10.1126/science.aaf2807
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.Keywords
Funding Information
- Robertson Foundation–Cancer Research Institute Irvington Fellowship
- American Cancer Society Postdoctoral Fellowship
- German Research Foundation Fellowship (BE5496/1-1)
- National Institutes of Health (F30DK100159, T32 2T32CA009615-26, CA78831, AI105343, AI112521, AI082630, AI115712, AI117950, AI108545)
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