title: Dasatinib enhances migration of monocyte-derived dendritic cells by reducing phosphorylation of inhibitory immune receptors Siglec-9 and Siglec-3.
abstract: The SRC family of kinases (SFKs) is crucial to malignant growth, but also important for signaling in immune cells such as dendritic cells (DCs). These specialized antigen-presenting cells are essential for inducing and boosting specific T-cell responses against pathogens and malignancies. Targeted therapy with SFK inhibitors holds great promise as a direct anti-cancer treatment, but potentially also as an indirect treatment via immunomodulation. Here, we investigated whether the BCR-ABL/SRC inhibitor dasatinib would modulate the major effector functions of DCs, especially their migration, a prerequisite to interaction with lymphocytes in secondary lymphoid organs. We report for the first time that dasatinib more than doubled the number of mature human monocyte-derived DCs (moDCs) migrating toward a CCL19 gradient despite unchanged CCR7 expression when used for pretreatment. These effects were caused by dephosphorylation of SFKs, as confirmed by the specific SFK inhibitor SRC inhibitor 1, leading to dephosphorylation of the inhibitory immunoreceptors Siglec-9 and Siglec-3. The specific blocking of the latter also enhanced migration and underlined the importance of these SFK-dependent receptor systems for migration of moDCs. Dasatinib hampered the secretion of interleukin-12 by moDCs at clinically relevant concentrations. In contrast, endocytosis or boosting of cytomegalovirus-specific CD8(+) T-cell responses remained unaltered when applying dasatinib-pretreated moDCs, in line with minor effects on the expression of co-stimulatory molecules essential for DC-T cell interaction. The induction of enhanced migration of moDCs may potentially be useful in chemo-immunotherapeutic applications. Thus, the use of dasatinib or blocking Siglec antibodies as adjuvants in this setting to induce stronger immune responses is worthy of further study.
authors.affiliation: Immune Recovery Section, Division of Hematology, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany; Comprehensive Cancer Center Mainfranken (CCC MF), University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nerreter
authors.affiliation: Immune Recovery Section, Division of Hematology, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Köchel
authors.affiliation: Immune Recovery Section, Division of Hematology, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jesper
authors.affiliation: Immune Recovery Section, Division of Hematology, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Eichelbrönner
authors.affiliation: Department of Transfusion Medicine, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Putz
authors.affiliation: Immune Recovery Section, Division of Hematology, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Comprehensive Cancer Center Mainfranken (CCC MF), University Hospital of Würzburg, Würzburg, Germany. Electronic address: Seggewiss_R@medizin.uni-wuerzburg.de.
authors.forename: Ruth
authors.initials: R
authors.lastname: Seggewiss-Bernhardt
mesh_terms: D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D054415:Chemokine CCL19 / Q000276:immunology / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects* / Q000276:immunology; D003587:Cytomegalovirus / Q000276:immunology / Q000378:metabolism; D000069439:Dasatinib; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D054400:Receptors, CCR7 / Q000276:immunology / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology / Q000378:metabolism*; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000276:immunology / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C515460:CCL19 protein, human; C515370:CCR7 protein, human; D054415:Chemokine CCL19; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D054400:Receptors, CCR7; C412227:SIGLEC9 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D013844:Thiazoles; D018664:Interleukin-12; D019061:src-Family Kinases; D000069439:Dasatinib