title: Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds.
abstract: As multiple myeloma (MM) progresses, natural killer (NK)-cell responses decline against malignant plasma cells. The immunomodulatory drug lenalidomide is widely used for treatment of MM but its influence on NK-cell biology is unclear. Here, we report that lenalidomide lowers the threshold for NK-cell activation, causing a 66% decrease in the 50% effective concentration (EC50) for activation through CD16, and a 38% decrease in EC50 for NK group 2 member D (NKG2D)-mediated activation, allowing NK cells to respond to lower doses of ligand. In addition, lenalidomide augments NK-cell responses, causing a twofold increase in the proportion of primary NK cells producing interferon-γ (IFN-γ), and a 20-fold increase in the amount of IFN-γ produced per cell. Importantly, lenalidomide did not trigger IFN-γ production in unstimulated NK cells. Thus, lenalidomide enhances the NK-cell arm of the immune response, without activating NK cells inappropriately. Of particular clinical importance, lenalidomide also allowed NK cells to be activated by lower doses of rituximab, an anti-CD20 monoclonal antibody (mAb) widely used to treat B-cell malignancies. This supports combined use of lenalidomide and rituximab in a clinical setting. Finally, superresolution microscopy revealed that lenalidomide increased the periodicity of cortical actin at immune synapses, resulting in an increase in the area of the actin mesh predicted to be penetrable to vesicles containing IFN-γ. NK cells from MM patients also responded to lenalidomide in this way. This indicates that nanometer-scale rearrangements in cortical actin, a recently discovered step in immune synapse assembly, are a potential new target for therapeutic compounds.
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, United Kingdom; Department of Life Sciences, Imperial College London, London, United Kingdom; and.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Lagrue
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, United Kingdom;
authors.forename: Alex
authors.initials: A
authors.lastname: Carisey
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, United Kingdom;
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgan
authors.affiliation: Department of Translational Development, Celgene Corporation, Summit, NJ.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, United Kingdom;
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Davis
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D002478:Cells, Cultured; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D054992:Immunological Synapses / Q000187:drug effects; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000077269:Lenalidomide; D008213:Lymphocyte Activation / Q000187:drug effects*; D018655:Lymphocyte Count; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000199:Actins; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D017452:Receptors, IgG; D013792:Thalidomide; D007371:Interferon-gamma; D000077269:Lenalidomide