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

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

doi:10.1126/science.aaf2807

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

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

Dean's Office - College of Arts & Science

University at Albany

University of Pennsylvania
Dana-Farber Cancer Institute
Harvard University
University of Minnesota Twin Cities
Broad Institute
Boston Children's Hospital

Research output: Contribution to journal › Article › peer-review

1069 Scopus citations

Abstract

Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 Tcells (T_EX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram T_EX into durable memory T cells (T_MEM) is unclear. We found that reinvigoration of T_EX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated T_EX became reexhausted if antigen concentration remained high and failed to become T_MEM upon antigen clearance. T_EX acquired an epigenetic profile distinct from that of effector T cells (T_EFF) and T_MEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that T_EX 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_EX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.

Original language	English
Pages (from-to)	1160-1165
Number of pages	6
Journal	Science
Volume	354
Issue number	6316
DOIs	https://doi.org/10.1126/science.aaf2807
State	Published - Dec 2 2016

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Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne, S., Godec, J., Khan, O., Drake, A. M., Chen, Z., Sen, D. R., Kurachi, M., Barnitz, R. A., Bartman, C., Bengsch, B., Huang, A. C., Schenkel, J. M., Vahedi, G., Haining, W. N., Berger, S. L., & Wherry, E. J. (2016). Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science, 354(6316), 1160-1165. https://doi.org/10.1126/science.aaf2807

@article{bb55af0f5d4546bb9ffa3156cbf4ce29,

title = "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 Tcells (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.",

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

year = "2016",

month = dec,

day = "2",

doi = "10.1126/science.aaf2807",

language = "English",

volume = "354",

pages = "1160--1165",

journal = "Science",

issn = "0036-8075",

number = "6316",

}

Pauken, KE, Sammons, MA, Odorizzi, PM, Manne, S, Godec, J, Khan, O, Drake, AM, Chen, Z, Sen, DR, Kurachi, M, Barnitz, RA, Bartman, C, Bengsch, B, Huang, AC, Schenkel, JM, Vahedi, G, Haining, WN, Berger, SL & Wherry, EJ 2016, 'Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade', Science, vol. 354, no. 6316, pp. 1160-1165. https://doi.org/10.1126/science.aaf2807

TY - JOUR

T1 - Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade

AU - Pauken, Kristen E.

AU - Sammons, Morgan A.

AU - Odorizzi, Pamela M.

AU - Manne, Sasikanth

AU - Godec, Jernej

AU - Khan, Omar

AU - Drake, Adam M.

AU - Chen, Zeyu

AU - Sen, Debattama R.

AU - Kurachi, Makoto

AU - Barnitz, R. Anthony

AU - Bartman, Caroline

AU - Bengsch, Bertram

AU - Huang, Alexander C.

AU - Schenkel, Jason M.

AU - Vahedi, Golnaz

AU - Haining, W. Nicholas

AU - Berger, Shelley L.

AU - Wherry, E. John

PY - 2016/12/2

Y1 - 2016/12/2

N2 - 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 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.

AB - 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 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.

UR - https://www.scopus.com/pages/publications/84994364943

U2 - 10.1126/science.aaf2807

DO - 10.1126/science.aaf2807

M3 - Article

C2 - 27789795

SN - 0036-8075

VL - 354

SP - 1160

EP - 1165

JO - Science

JF - Science

IS - 6316

ER -

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

Abstract

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