title: Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor-induced interleukin 12 synthesis.
abstract: Src-kinase inhibitors hold great potential as targeted therapy against malignant cells. However, such inhibitors may also affect nonmalignant cells and cause pronounced off-target effects. We investigated the role of the dual kinase inhibitor dasatinib on human myeloid cells. Dasatinib is clinically used for the treatment of bcr/abl⁺ leukemias because it blocks the mutated tyrosine kinase abl. To understand its effect on the development of antigen-specific T-cell responses, we assessed antigen-specific priming of human, naïve T cells. In surprising contrast to the direct inhibition of T-cell activation by dasatinib, pretreatment of maturing dendritic cells (DCs) with dasatinib strongly enhanced their stimulatory activity. This effect strictly depended on the activating DC stimulus and led to enhanced interleukin 12 (IL-12) production and T-cell responses of higher functional avidity. Src-kinase inhibitors, and not conventional tyrosine kinase inhibitors, increased IL-12 production in several cell types of myeloid origin, such as monocytes and classical or nonclassical DCs. Interestingly, only human cells, but not mouse or macaques DCs, were affected. These data highlight the potential immunostimulatory capacity of a group of novel drugs, src-kinase inhibitors, thereby opening new opportunities for chemoimmunotherapy. These data also provide evidence for a regulatory role of src kinases in the activation of myeloid cells.
authors.affiliation: Children's Hospital, Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Würzburg, Würzburg, Germany. woelfl_m@klinik.uni-wuerzburg.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Wölfl
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schwinn
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Yoo
authors.forename: Marie L
authors.initials: ML
authors.lastname: Reß
authors.forename: Matthias
authors.initials: M
authors.lastname: Braun
authors.forename: Martin
authors.initials: M
authors.lastname: Chopra
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Schreiber
authors.forename: Victor I
authors.initials: VI
authors.lastname: Ayala
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlen
authors.forename: Matthias
authors.initials: M
authors.lastname: Eyrich
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
authors.forename: Paul G
authors.initials: PG
authors.lastname: Schlegel
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000069439:Dasatinib; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D008253:Macaca mulatta; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology*; D051193:Toll-Like Receptors / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D051193:Toll-Like Receptors; D018664:Interleukin-12; D019061:src-Family Kinases; D000069439:Dasatinib