Enhancement of natural killer cell effector functions against selected lymphoma and leukemia cell lines by dasatinib

Authors

  • Nicole Hassold,

    1. Immune Recovery Section, Comprehensive Cancer Center (CCC), Department of Internal Medicine II, University of Würzburg, Würzburg, Germany
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  • Katharina Seystahl,

    1. Immune Recovery Section, Comprehensive Cancer Center (CCC), Department of Internal Medicine II, University of Würzburg, Würzburg, Germany
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    • K.S. and K.K. contributed equally to this work

  • Kristina Kempf,

    1. Immune Recovery Section, Comprehensive Cancer Center (CCC), Department of Internal Medicine II, University of Würzburg, Würzburg, Germany
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    • K.S. and K.K. contributed equally to this work

  • Doris Urlaub,

    1. Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany
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  • Michael Zekl,

    1. Immune Recovery Section, Comprehensive Cancer Center (CCC), Department of Internal Medicine II, University of Würzburg, Würzburg, Germany
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  • Hermann Einsele,

    1. Immune Recovery Section, Comprehensive Cancer Center (CCC), Department of Internal Medicine II, University of Würzburg, Würzburg, Germany
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  • Carsten Watzl,

    1. Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany
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  • Jörg Wischhusen,

    1. Interdisciplinary Center for Clinical Research, Department for Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany
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  • Ruth Seggewiss-Bernhardt

    Corresponding author
    1. Immune Recovery Section, Comprehensive Cancer Center (CCC), Department of Internal Medicine II, University of Würzburg, Würzburg, Germany
    • Comprehensive Cancer Center (CCC), Department of Internal Medicine II, University of Würzburg, C11, Room E02, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany
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    • Tel.: 49-931-201-36402, Fax: +49-931-201-36409


Abstract

As NK cell immunotherapy is still poorly successful, combinations with drugs enhancing NK cell activity are of major interest. NK large granular lymphocyte expansions associated with improved survival have been described under monotherapy with the Bcr-Abl/Src inhibitor dasatinib, which inhibits NK cell functions in vitro. As Src kinases play a major role in inhibitory and activating signaling pathways of NK cells, both outcomes appear plausible. To clarify these contradictory observations and potentially enable the use of dasatinib as adjuvant, we analyzed how clinically relevant doses promote NK cell effector functions. Polyclonal human NK cells were studied ex vivo. Functional outcomes assessed included conjugate formation, calcium flux, receptor regulation, cytokine production, degranulation, cytotoxicity, apoptosis induction and signal transduction. While dasatinib inhibits NK cell effector functions during functional assays, 24 hr pretreatment of NK cells followed by washout of dasatinib, led to dose-dependent enhancement of cytokine production, degranulation marker expression and cytotoxicity against selected lymphoma and leukemia cell lines. Mechanistically, this was neither due to an altered viability of NK cells nor increased NKG2D, LFA-1 or conjugate formation with target cells. Receptor proximal signaling events were inhibited. However, a slight time dependent enhancement of Vav phosphorylation was observed under certain circumstances. The shift in Vav phosphorylation level may be one major mechanism for NK cell activity enhancement induced by dasatinib. Our findings argue for a careful timing and dosing of dasatinib application during leukemia/lymphoma treatment to enhance NK cell immunotherapeutic efforts.

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