PD-1 Signaling on Chronic Myeloid Leukemia-Specific T Cells Results in T Cell Exhaustion and Disease Progression.

Chronic myeloid leukemia (CML) is a malignant myeloproliferative disease of hematopoietic stem cells with a characteristic chronic phase of several years before progression to acute myeloid leukemia. The immune system may contribute to disease control at this stage. Here we analyzed leukemia-specific immune responses in a murine retroviral bone marrow transduction and transplantation model using the glycoprotein of lymphocytic choriomeningitis virus as a model leukemia antigen. We found that CML-specific cytotoxic T cells (CTLs) became exhausted after initial activation and expansion. Only a small fraction of CML-specific CTLs persisted longterm. They maintained some limited cytotoxic activity but did not produce IFNγ or TNFα or expand after restimulation. CML-specific CTLs were characterized by high expression of programmed death 1 (PD-1), whereas CML cells expressed PD-ligand 1 (PD-L1). Blocking PD-1 signaling in CML mice by transferring BCR/ABL-NUP98/HOXA9 transduced bone marrow cells to PD-1 deficient recipient mice resulted in improved CML disease control and prolonged survival. In addition, we extended our findings from the preclinical CML model to human patients. PD-1 was expressed at significantly higher levels on CD8+ T cells of CML patients when compared to healthy donors. These data identify PD-1 as a potential target to restore the function of exhausted CML-specific CTLs and therefore to treat CML.