PD-1 signaling on chronic myeloid leukemia-specific T cells results in T cell exhaustion and disease progression.
Blood. 2009 May 6. [Epub ahead of print]
Mumprecht S, Schurch C, Schwaller J, Solenthaler M, Ochsenbein AF.
Tumor Immunology, Department of Clinical Research, University of Berne, Berne, Switzerland.
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 cp and bcCML in a retroviral-induced murine CML model. In the presence of cp and bcCML expressing the glycoprotein of lymphocytic choriomeningitis virus (LCMV) as a model leukemia antigen, leukemia-specific cytotoxic T lymphocytes (CTLs) became exhausted. They maintained only limited cytotoxic activity, did not produce IFN-gamma or TNF-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 alphaPD-L1 antibody prolonged survival. In addition, we found that PD-1 is upregulated 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. |
