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

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 c...

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Veröffentlicht in:Cancer Immunology, Immunotherapy Immunotherapy, 2016-03, Vol.65 (3), p.273-282
Hauptverfasser: Heine, Annkristin, Schilling, Judith, Grünwald, Barbara, Krüger, Achim, Gevensleben, Heidrun, Held, Stefanie Andrea Erika, Garbi, Natalio, Kurts, Christian, Brossart, Peter, Knolle, Percy, Diehl, Linda, Höchst, Bastian
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container_end_page 282
container_issue 3
container_start_page 273
container_title Cancer Immunology, Immunotherapy
container_volume 65
creator Heine, Annkristin
Schilling, Judith
Grünwald, Barbara
Krüger, Achim
Gevensleben, Heidrun
Held, Stefanie Andrea Erika
Garbi, Natalio
Kurts, Christian
Brossart, Peter
Knolle, Percy
Diehl, Linda
Höchst, Bastian
description 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.
doi_str_mv 10.1007/s00262-015-1790-5
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subjects Cancer
Cancer Research
Celecoxib - pharmacology
Cell Differentiation - drug effects
Cells, Cultured
Dasatinib - pharmacology
Dose-Response Relationship, Drug
Hematology
Hepatic Stellate Cells - physiology
Humans
Immune system
Immune Tolerance
Immunology
Immunotherapy
Indoles - pharmacology
Leukemia
Medical prognosis
Medicine
Medicine & Public Health
Monocytes - physiology
Myeloid Cells - drug effects
Myeloid Cells - immunology
Niacinamide - analogs & derivatives
Niacinamide - pharmacology
Oncology
Original
Original Article
Phenylurea Compounds - pharmacology
Protein Kinase Inhibitors - pharmacology
Pyrimidines - pharmacology
Pyrroles - pharmacology
Sorafenib
Sunitinib
title 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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