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 (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.