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

S Mumprecht, C Schürch, J Schwaller… - Blood, The Journal …, 2009 - ashpublications.org
S Mumprecht, C Schürch, J Schwaller, M Solenthaler, AF Ochsenbein
Blood, The Journal of the American Society of Hematology, 2009ashpublications.org
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) …
Abstract
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-γ or tumor necrosis factor-α 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 αPD-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.
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