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

  • Science. 2016 Dec 2;354(6316):1160-1165. doi: 10.1126/science.aaf2807.
Kristen E Pauken  1 ,  Morgan A Sammons  2 ,  Pamela M Odorizzi  1 ,  Sasikanth Manne  1 ,  Jernej Godec  3  4 ,  Omar Khan  1 ,  Adam M Drake  2 ,  Zeyu Chen  1 ,  Debattama R Sen  3 ,  Makoto Kurachi  1 ,  R Anthony Barnitz  3 ,  Caroline Bartman  1 ,  Bertram Bengsch  1 ,  Alexander C Huang  5 ,  Jason M Schenkel  6 ,  Golnaz Vahedi  7 ,  W Nicholas Haining  3  8  9 ,  Shelley L Berger  2 ,  E John Wherry  10
Affiliations
  • 1. Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 2. Departments of Cell and Developmental Biology, Genetics, and Biology, Penn Epigenetics Program, University of Pennsylvania, Philadelphia, PA, USA.
  • 3. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
  • 5. Department of Medicine and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 6. Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA.
  • 7. Department of Genetics and Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA.
  • 8. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 9. Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 10. Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
PMID: 27789795 DOI: 10.1126/science.aaf2807
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 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.