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

Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (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.
(Copyright © 2016, American Association for the Advancement of Science.)