Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade

Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (T ) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram T into durable memory T cells (T ) is unclear. We found that reinvigoration of T in mice by PD-L1 blockade caused minimal...

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Vydáno v:	Science (American Association for the Advancement of Science) Ročník 354; číslo 6316; s. 1160
Hlavní autoři:	Pauken, Kristen E, Sammons, Morgan A, Odorizzi, Pamela M, Manne, Sasikanth, Godec, Jernej, Khan, Omar, Drake, Adam M, Chen, Zeyu, Sen, Debattama R, Kurachi, Makoto, Barnitz, R Anthony, Bartman, Caroline, Bengsch, Bertram, Huang, Alexander C, Schenkel, Jason M, Vahedi, Golnaz, Haining, W Nicholas, Berger, Shelley L, Wherry, E John
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 02.12.2016
Témata:	Animals B7-H1 Antigen - antagonists & inhibitors B7-H1 Antigen - genetics CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - transplantation Cell Lineage - genetics Cellular Reprogramming - genetics Cellular Reprogramming - immunology Epigenesis, Genetic Female Gene Regulatory Networks Immunologic Memory - genetics Immunotherapy Interleukin-7 - metabolism Mice Mice, Inbred C57BL Transcription, Genetic
ISSN:	1095-9203, 1095-9203
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Shrnutí:	Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (T ) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram T into durable memory T cells (T ) is unclear. We found that reinvigoration of T in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated T became reexhausted if antigen concentration remained high and failed to become T upon antigen clearance. T acquired an epigenetic profile distinct from that of effector T cells (T ) and T cells that was minimally remodeled after PD-L1 blockade. This finding suggests that T are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the T epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1095-9203 1095-9203
DOI:	10.1126/science.aaf2807