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The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Increased numbers of immunosuppressive myeloid derived suppressor cells (MDSCs) correlate with a poor prognosis in cancer patients. Tyrosine kinase inhibitors (TKIs) are used as standard therapy for the treatment of several neoplastic diseases. However, TKIs not only exert effects on the malignant cell clone itself but also affect immune cells. Here, we investigate the effect of TKIs on the induction of MDSCs that differentiate from mature human monocytes using a new in vitro model of MDSC induction through activated hepatic stellate cells (HSCs). We show that frequencies of monocytic CD14+HLA-DR−/low MDSCs derived from mature monocytes were significantly and dose-dependently reduced in the presence of dasatinib, nilotinib and sorafenib, whereas sunitinib had no effect. These regulatory effects were only observed when TKIs were present during the early induction phase of MDSCs through activated HSCs, whereas already differentiated MDSCs were not further influenced by TKIs. Neither the MAPK nor the NFκB pathway was modulated in MDSCs when any of the TKIs was applied. When functional analyses were performed, we found that myeloid cells treated with sorafenib, nilotinib or dasatinib, but not sunitinib, displayed decreased suppressive capacity with regard to CD8+ T cell proliferation. Our results indicate that sorafenib, nilotinib and dasatinib, but not sunitinib, decrease the HSC-mediated differentiation of monocytes into functional MDSCs. Therefore, treatment of cancer patients with these TKIs may in addition to having a direct effect on cancer cells also prevent the differentiation of monocytes into MDSCs and thereby differentially modulate the success of immunotherapeutic or other anti-cancer approaches.

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Abbreviations

atRA:

All-trans retinoic acid

CML:

Chronic myeloid leukemia

Cox-2:

Cyclo-oxygenase-2

es. ph.:

Established phase

Gr-1high :

CD11b+Ly-6G+Ly-6Clow

Gr-1low :

CD11b+Ly-6G−Ly-6Chigh

HSC:

Hepatic stellate cell

in. ph.:

Induction phase

LPS:

Lipopolysaccharides

MDSC:

Myeloid derived suppressor cell

MoDC:

Monocyte derived dendritic cell

NFκB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

PBMC:

Peripheral blood mononuclear cells

PD-1:

Programmed death 1

TKI:

Tyrosine kinase inhibitor

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Acknowledgments

We thank Kati Riethausen, Solveig Daecke and Daniel Schätzlein for the excellent technical support. This study was supported by a grant from BONFOR Forschungsförderung (Annkristin Heine & Bastian Höchst).

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Authors and Affiliations

  1. Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany

    Annkristin Heine, Stefanie Andrea Erika Held & Peter Brossart

  2. Institute of Molecular Medicine, University Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany

    Judith Schilling, Percy Knolle & Bastian Höchst

  3. Institute for Pathology, University Hospital Bonn, Bonn, Germany

    Heidrun Gevensleben

  4. Institute of Experimental Immunology, University Bonn, Bonn, Germany

    Annkristin Heine, Natalio Garbi & Christian Kurts

  5. Institute for Molecular Immunology and Experimental Oncology, Technische Universität München, Munich, Germany

    Barbara Grünwald, Achim Krüger, Percy Knolle & Bastian Höchst

  6. Institute of Experimental Immunology and Hepatology, University Hamburg Eppendorf, Hamburg, Germany

    Linda Diehl

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  1. Annkristin Heine
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Correspondence to Annkristin Heine or Bastian Höchst.

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Heine, A., Schilling, J., Grünwald, B. et al. The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib. Cancer Immunol Immunother 65, 273–282 (2016). https://doi.org/10.1007/s00262-015-1790-5

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