title: Modulation of natural killer cell effector functions through lenalidomide/dasatinib and their combined effects against multiple myeloma cells.
abstract: The multikinase inhibitor dasatinib blocks the constitutive activation of oncogenic Src kinases in multiple myeloma (MM) cells and potentially enhances natural killer (NK) cell activity. Therefore, we tested combination effects of dasatinib and lenalidomide regarding MM cell viability and NK cell effector functions. The drug combination mostly had little influence on the viability of MM cell lines, and produced mixed results on primary MM cells. Prolonged lenalidomide treatment enhanced NK cell effector functions, and dasatinib addition at late stages of NK cell expansion increased levels of CD107a/b and interferon-γ (IFNγ), but not of tumor necrosis factor-α (TNFα). Additive effects were observed for the enhancement of cytokine production and degranulation, but only lenalidomide increased NK cell cytotoxicity against MM cells. This effect correlated with increased TNF-related apoptosis-inducing ligand (TRAIL) expression and was attenuated by dasatinib, or suppressors of TRAIL or TNFα. Our data thus indicate a functional role for the TRAIL/TRAIL-R system in lenalidomide-mediated NK-cell activity against MM cells, but also show that dasatinib is unsuitable to support or boost this effect.
authors.affiliation: Immune Recovery Section, Division of Hematology.
authors.forename: Isabel
authors.initials: I
authors.lastname: Jungkunz-Stier
authors.forename: Michael
authors.initials: M
authors.lastname: Zekl
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stühmer
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Ruth
authors.initials: R
authors.lastname: Seggewiss-Bernhardt
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D000069439:Dasatinib; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000633:toxicity; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D000077269:Lenalidomide; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000633:toxicity; D011743:Pyrimidines / Q000494:pharmacology* / Q000633:toxicity; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D013844:Thiazoles / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D052118:Lysosomal-Associated Membrane Protein 1; D052119:Lysosomal-Associated Membrane Protein 2; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053221:TNF-Related Apoptosis-Inducing Ligand; D013844:Thiazoles; D013792:Thalidomide; D000077269:Lenalidomide; D000069439:Dasatinib