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 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEXinto durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEXin mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEXbecame reexhausted if antigen concentration remained high and failed to become TMEMupon antigen clearance. TEXacquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEMcells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEXare a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEXepigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Kristen E
authors: KE
authors: Pauken
authors: Departments of Cell and Developmental Biology, Genetics, and Biology, Penn Epigenetics Program, University of Pennsylvania, Philadelphia, PA, USA.
authors: Morgan A
authors: MA
authors: Sammons
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Pamela M
authors: PM
authors: Odorizzi
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Sasikanth
authors: S
authors: Manne
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
authors: Jernej
authors: J
authors: Godec
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Omar
authors: O
authors: Khan
authors: Departments of Cell and Developmental Biology, Genetics, and Biology, Penn Epigenetics Program, University of Pennsylvania, Philadelphia, PA, USA.
authors: Adam M
authors: AM
authors: Drake
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Zeyu
authors: Z
authors: Chen
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Debattama R
authors: DR
authors: Sen
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Makoto
authors: M
authors: Kurachi
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: R Anthony
authors: RA
authors: Barnitz
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Caroline
authors: C
authors: Bartman
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Bertram
authors: B
authors: Bengsch
authors: Department of Medicine and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Alexander C
authors: AC
authors: Huang
authors: Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA.
authors: Jason M
authors: JM
authors: Schenkel
authors: Department of Genetics and Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA.
authors: Golnaz
authors: G
authors: Vahedi
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors: W Nicholas
authors: WN
authors: Haining
authors: Departments of Cell and Developmental Biology, Genetics, and Biology, Penn Epigenetics Program, University of Pennsylvania, Philadelphia, PA, USA.
authors: Shelley L
authors: SL
authors: Berger
authors: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@mail.med.upenn.edu.
authors: E John
authors: EJ
authors: Wherry
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D019070:Cell Lineage / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics* / Q000276:immunology; D044127:Epigenesis, Genetic; D005260:Female; D053263:Gene Regulatory Networks; D007156:Immunologic Memory / Q000235:genetics*; D007167:Immunotherapy; D015851:Interleukin-7 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014158:Transcription, Genetic
chemical_list: D060890:B7-H1 Antigen; D015851:Interleukin-7