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.
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.
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany. annkristin.heine@ukb.uni-bonn.de.|Institute of Experimental Immunology, University Bonn, Bonn, Germany. annkristin.heine@ukb.uni-bonn.de.
authors.forename: Annkristin
authors.initials: A
authors.lastname: Heine
authors.affiliation: Institute of Molecular Medicine, University Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Schilling
authors.affiliation: Institute for Molecular Immunology and Experimental Oncology, Technische Universität München, Munich, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Grünwald
authors.affiliation: Institute for Molecular Immunology and Experimental Oncology, Technische Universität München, Munich, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Krüger
authors.affiliation: Institute for Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Gevensleben
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany.
authors.forename: Stefanie Andrea Erika
authors.initials: SA
authors.lastname: Held
authors.affiliation: Institute of Experimental Immunology, University Bonn, Bonn, Germany.
authors.forename: Natalio
authors.initials: N
authors.lastname: Garbi
authors.affiliation: Institute of Experimental Immunology, University Bonn, Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
authors.affiliation: Institute of Molecular Medicine, University Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany.|Institute for Molecular Immunology and Experimental Oncology, Technische Universität München, Munich, Germany.
authors.forename: Percy
authors.initials: P
authors.lastname: Knolle
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Diehl
authors.affiliation: Institute of Molecular Medicine, University Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany. Bastian.Hoechst@tum.de.|Institute for Molecular Immunology and Experimental Oncology, Technische Universität München, Munich, Germany. Bastian.Hoechst@tum.de.
authors.forename: Bastian
authors.initials: B
authors.lastname: Höchst
mesh_terms: D000068579:Celecoxib / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D000069439:Dasatinib / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055166:Hepatic Stellate Cells / Q000502:physiology*; D006801:Humans; D007108:Immune Tolerance; D007211:Indoles / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000077157:Sorafenib; D000077210:Sunitinib
chemical_list: D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; C498826:nilotinib; D000068579:Celecoxib; D000069439:Dasatinib; D000077210:Sunitinib
keywords: Immunomodulation; Immunotherapy; Myeloid derived suppressor cells; Tyrosine kinase inhibitors