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The BCR-ABL inhibitor nilotinib influences phenotype and function of monocyte-derived human dendritic cells

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Abstract

In chronic myeloid leukemia (CML), the translocation t(9;22) results in the fusion protein BCR-ABL (breakpoint cluster region-abelson murine leukemia), a tyrosine kinase mediating oncogenic signaling which is successfully targeted by treatment with BCR-ABL inhibitors like imatinib. However, BCR-ABL inhibitors may also affect antitumor immunity. For instance, it was reported that imatinib impairs the function of dendritic cells (DCs) that play a central role in initiating and sustaining T cell responses. Meanwhile, second generation BCR-ABL inhibitors like nilotinib, which inhibits BCR-ABL with enhanced potency have become standard of treatment, at least in patients with BCR-ABL kinase domain mutations. In this study we analyzed the influence of therapeutic concentrations of nilotinib on human monocyte-derived DCs and compared its effects to imatinib. We found that both tyrosine kinase inhibitors (TKI) comparably and significantly impaired differentiation of monocytes to DCs as revealed by curtated downregulation of CD14 and reduced upregulation of CD1a and CD83. This was only partially restored after withdrawal of the TKI. Moreover, both TKI significantly reduced activation-induced IL-12p70 and C-C motif chemokine ligand (CCL) 3 secretion, while divergent TKI effects for CCL2 and CCL5 were observed. In contrast, only nilotinib significantly impaired the migratory capacity of DCs and their capacity to induce T-cell immune responses in MLRs. Our results indicate that imatinib and nilotinib may differ significantly with regard to their influence on antitumor immunity. Thus, for future combinatory approaches and particularly stop studies in CML treatment, choice of the most suitable BCR-ABL inhibitor requires careful consideration.

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Abbreviations

BB515:

Brilliant blue 515

BCR-ABL:

Breakpoint cluster region-abelson murine leukemia

CCL:

C-C motif chemokine ligand

CCR:

C-C motif chemokine receptor

CML:

Chronic myeloid leukemia

DC:

Dendritic cell

DMFI:

Delta MFI

FSC:

Forward scatter

GITR/GITRL:

Glucocorticoid-induced tumor necrosis factor receptor/-ligand

HLA-DR:

Human leukocyte antigen–antigen D related

MIP-3β:

Macrophage-inflammatory protein 3β

RANK:

Receptor activator of NF-κB

RANKL:

Receptor activator of NF-κB ligand

SSC:

Side scatter

TKI:

Tyrosine kinase inhibitor

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Acknowledgements

We thank Sylvia Klein for excellent technical assistance as well as Lothar Kanz for critical reading of the manuscript.

Funding

Susanne M. Rittig was supported by the Deutsche Krebshilfe (Grant 109046), Wilhelm Sander Stiftung (Grant 2013.148.1) as well as the European Social Fund.

Author information

Author notes

  1. Christian J. Lechner

    Present address: Medizin & Markt GmbH, Munich, Germany

  2. Simone Joas

    Present address: Institute of Molecular Virology, Ulm University Hospital, Ulm, Germany

  3. Michael Gutknecht

    Present address: Novartis Pharma AG, Basel, Switzerland

  4. Susanne M. Rittig

    Present address: Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany

Authors and Affiliations

  1. Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tübingen, Tübingen, Germany

    Daniela Dörfel, Korbinian N. Kropp, Stefanie Maurer & Helmut R. Salih

  2. Department of Medical Oncology, Hematology, Immunology, Rheumatology and Pulmology, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076, Tübingen, Germany

    Daniela Dörfel, Christian J. Lechner, Simone Joas, Tanja Funk, Michael Gutknecht, Julia Salih, Julian Geiger, Martin R. Müller, Hans-Georg Kopp, Helmut R. Salih, Frank Grünebach & Susanne M. Rittig

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  1. Daniela Dörfel
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Contributions

SMR, CJL, SJ, TF, MG, JS, JG, and SM designed and performed the experiments and analyzed data. DD, KNK, SMR, and HRS analyzed data and wrote the manuscript. MRM, H-GK, HRS, FG designed research, analyzed data and provided important advice.

Corresponding author

Correspondence to Susanne M. Rittig.

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The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

This study was approved by the local institutional review board (344/2008BO2; Ethics Committee at the Medical Faculty and at the University Hospital Tübingen). Buffy coat preparations were produced by the local blood bank after obtaining informed consent, in accordance with the principles of the Declaration of Helsinki and its later amendments.

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Dörfel, D., Lechner, C.J., Joas, S. et al. The BCR-ABL inhibitor nilotinib influences phenotype and function of monocyte-derived human dendritic cells. Cancer Immunol Immunother 67, 775–783 (2018). https://doi.org/10.1007/s00262-018-2129-9

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