@article{c305b95096cc4ce5b00326d8af07228e,
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}",
note = "Funding Information: We thank the Wherry lab for discussions and critically reading the manuscript. We thank C. Surh for providing the antibody against IL-7 (anti-IL-7). The anti-IL-7 antibody is available from La Jolla Institute of Allergy and Immunology, and the IL-7 used is available from the National Cancer Institute, both under material transfer agreements with the University of Pennsylvania. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. Sequencing data are available at Gene Expression Omnibus [accession numbers GSE86796 (microarray), GSE86881 (RNA seq), and GSE86797 (ATAC seq)]. This study was supported by a Robertson Foundation - Cancer Research Institute Irvington Fellowship (K.E.P.), an American Cancer Society Postdoctoral Fellowship (M.A.S.), National Institutes of Health grant F30DK100159 (J.M.S.), German Research Foundation Fellowship BE5496/1-1 (B.B.), and National Institutes of Health grant T32 2T32CA009615-26 (A.C.H.). This work was funded by the National Institutes of Health (grant CA78831 to S.L.B. and grants AI105343, AI112521, AI082630, AI115712, AI117950, and AI108545 to E.J.W.). This research was also supported by the Parker Institute for Cancer Immunotherapy. E.J.W. has a patent licensing agreement on the PD-1 pathway. The authors declare no additional conflicts of interest. Publisher Copyright: {\textcopyright} 2016, American Association for the Advancement of Science. All rights reserved.",
year = "2016",
month = dec,
day = "2",
doi = "10.1126/science.aaf2807",
language = "English (US)",
volume = "354",
pages = "1160--1165",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6316",
}