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.