The Kinase Inhibitor Imatinib - An Immunosuppressive Drug?

The phenylaminopyrimidine-derivate Imatinib mesylate has been developed for targeted inhibition of the Abelson kinase (c-ABL), which is constitutively activated when translocated to the genetic locus of the breakpoint cluster region (leading to the BCR/ABL fusion gene), thereby forming the causative pathogenetic event for the development of chronic myeloid leukemia (CML). Of note, due to its physico-chemical properties, kinase specificity of Imatinib is limited. Despite of its well documented clinical efficacy mediated by inhibition of constitutively activated tyrosine kinases such as BCR/ABL in CML, PDGF-RA in HES and mutated c-kit in GIST patients, other tyrosine kinases such as Flt-3, Lck and mitogen-activated kinases (MAPK) are affected as well. Accordingly, it has recently been shown that therapeutic doses of Imatinib also target a variety of immune cells, e.g. by modulating the differentiation of dendritic cells (DC) as well as by impeding proper T-cell and macrophage function. In contrast, combining Imatinib with Interleukin 2 (IL-2) potently activates NK-cells and led to the description of a new subclass of DC, so-called IK-DC. The latter mediate Imatinib/IL-2-induced regression of tumors in pre-clinical animal models via production of high amounts of IFN-γ and the death receptor ligand TRAIL. Thus, Imatinib exerts potent immuno-modulatory effects in vitro and in vivo, which will be discussed together with their clinical relevance in detail throughout this review.