Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.
Pauken KE , Sammons MA , Odorizzi PM , Manne S , Godec J , Khan O , Drake AM , Chen Z , Sen D , Kurachi M , Barnitz RA , Bartman C , Bengsch B , Huang AC , Schenkel JM , Vahedi G , Haining WN , Berger SL , Wherry EJ 
Science.2016 Oct 27 ; ():.
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Blocking PD-1 can re-invigorate 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 re-invigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, re-invigorated TEX became re-exhausted if antigen remained high, and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from effector (TEFF) and TMEM cells that was minimally remodeled following PD-L1 blockade. This suggests TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and re-engagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.
PMID: 27789795 [PubMed - as supplied by publisher]
PMID: 27789795 [PubMed - as supplied by publisher]
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