Dasatinib inhibits the proliferation and function of CD4+CD25+ regulatory T cells

Authors


Professor Dr med. Michael Schmitt, Head of Tumour Immunology Group, Department of Internal Medicine III, University of Ulm, Robert-Koch-Str 8, Ulm 89081, Germany. E-mail: michael.schmitt@uniklinik-ulm.de

Summary

CD4+CD25+ regulatory T cells (Tregs) can influence various immune responses. Little is known about the effects of the Abl/Src kinase inhibitor dasatinib on Tregs which regulate anti-tumor/leukaemia immune responses. The present study demonstrated that dasatinib inhibited proliferation of Tregs and CD4+CD25 T cells in a dose-dependent manner, which was associated with the decreased production of corresponding cytokines. Treatment of Tregs with dasatinib inhibited the suppressive capacity of Tregs. The mechanisms of this inhibition included arrest of cells in the G0/G1 phase of cell cycle, down-regulation of the transcription factor forkhead box P3, glucocorticoid-induced tumour necrosis factor receptor and the cytotoxic T lymphocyte associated protein 4 as well as inhibition of signaling events through Src and nuclear factor κB. Dasatinib showed an inhibitory effect on the proliferation and function of both Tregs and CD4+CD25 T cells at therapeutically relevant concentrations of the drug. Clinical administration of dasatinib might influence not only the graft-versus-leukaemia effect but also the graft-versus-host-disease in patients receiving dasatinib after allogeneic stem cell transplantation and/or donor lymphocytes infusion as the function of both Tregs and effector T cells are hampered in a similar way by dasatinib.

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