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...

Full description

Saved in:
Bibliographic Details
Published in:Science (American Association for the Advancement of Science) Vol. 354; no. 6316; p. 1160
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 02.12.2016
Subjects:
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
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1095-9203
1095-9203
DOI:10.1126/science.aaf2807