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

by Godec, Jernej , Khan, Omar , Vahedi, Golnaz , Chen, Zeyu , Berger, Shelley L. , Wherry, E. John , Odorizzi, Pamela M. , Bartman, Caroline , Sammons, Morgan A. , Huang, Alexander C. , Barnitz, R. Anthony , Schenkel, Jason M. , Bengsch, Bertram , Pauken, Kristen E. , Haining, W. Nicholas , Drake, Adam M. , Sen, Debattama R. , Kurachi, Makoto , Manne, Sasikanth

in Animals / Antigens / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - genetics / Cancer / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - transplantation / Cell Lineage - genetics / Cellular biology / Cellular Reprogramming - genetics / Cellular Reprogramming - immunology / Control / Durability / Effectors / Epigenesis, Genetic / Epigenetics / Exhaustion / Female / Gene Regulatory Networks / Immunologic Memory - genetics / Immunotherapy / Interleukin-7 - metabolism / Lymphocytes / Memory / Mice / Mice, Inbred C57BL / Rewiring / Transcription, Genetic

2016

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

2016

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

2016

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Journal Article

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

Godec, Jernej,

Khan, Omar,

Vahedi, Golnaz,

Chen, Zeyu,

Berger, Shelley L.,

Wherry, E. John,

Odorizzi, Pamela M.,

Bartman, Caroline,

Sammons, Morgan A.,

Huang, Alexander C.,

Barnitz, R. Anthony,

Schenkel, Jason M.,

Bengsch, Bertram,

Pauken, Kristen E.,

Haining, W. Nicholas,

Drake, Adam M.,

Sen, Debattama R.,

Kurachi, Makoto,

Manne, Sasikanth

2016

Overview

Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 Tcells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory Tcells (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 Tcells (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.

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Publisher

American Association for the Advancement of Science,The American Association for the Advancement of Science

Subject

Animals

/ Antigens

/ B7-H1 Antigen - antagonists & inhibitors

/ B7-H1 Antigen - genetics

/ Cancer

/ CD8-Positive T-Lymphocytes - immunology

/ CD8-Positive T-Lymphocytes - transplantation