Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression

Blood. 2009 Aug 20;114(8):1528-36. doi: 10.1182/blood-2008-09-179697. Epub 2009 May 6.


Chronic myeloid leukemia (CML) is a malignant myeloproliferative disease with a characteristic chronic phase (cp) of several years before progression to blast crisis (bc). The immune system may contribute to disease control in CML. We analyzed leukemia-specific immune responses in cpCML and bcCML in a retroviral-induced murine CML model. In the presence of cpCML and bcCML expressing the glycoprotein of lymphocytic choriomeningitis virus as a model leukemia antigen, leukemia-specific cytotoxic T lymphocytes (CTLs) became exhausted. They maintained only limited cytotoxic activity, and did not produce interferon-gamma or tumor necrosis factor-alpha 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 the PD-1/PD-L1 interaction by generating bcCML in PD-1-deficient mice or by repetitive administration of alphaPD-L1 antibody prolonged survival. In addition, we found that PD-1 is up-regulated on CD8(+) T cells from CML patients. Taken together, our results suggest that blocking the PD-1/PD-L1 interaction may restore the function of CML-specific CTLs and may represent a novel therapeutic approach for CML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antigens, Surface / genetics
  • Antigens, Surface / metabolism
  • Antigens, Surface / physiology*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis Regulatory Proteins / physiology*
  • Cells, Cultured
  • Disease Progression
  • Female
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Lymphocyte Count
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Models, Biological
  • Programmed Cell Death 1 Receptor
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • T-Lymphocytes / pathology*


  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor