Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor–induced interleukin 12 synthesis

• Published in: Blood 2013-08, Vol.122 (7), p.1203-1213
• Main Authors: Wölfl, Matthias, Schwinn, Stefanie, Yoo, Young-Eun, Reß, Marie L., Braun, Matthias, Chopra, Martin, Schreiber, Susanne C., Ayala, Victor I., Ohlen, Claes, Eyrich, Matthias, Beilhack, Andreas, Schlegel, Paul G.
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Dasatinib; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - pathology; Flow Cytometry; Humans; Immunobiology; Interleukin-12 - metabolism; Lymphocyte Activation - drug effects; Macaca mulatta; Mice; Myeloid Cells - drug effects; Myeloid Cells - immunology; Myeloid Cells - pathology; NF-kappa B - metabolism; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Pyrimidines - pharmacology; Signal Transduction - drug effects; src-Family Kinases - antagonists & inhibitors; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Thiazoles - pharmacology; Toll-Like Receptors - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2013-03-488072

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. •In contrast to their suppressive effects on T cells, src-kinase inhibitors strongly enhance IL-12 production in human myeloid cells.•This effect is synergistic to TLR2 or TLR4 signaling, whereas inhibition of src-kinases alone does not trigger DC activation.