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-g (IFN-g), and a 20-fold increase in the amount of IFN-g produced per cell. Importantly, lenalidomide did not trigger IFN-g production in unstimulatedNK cells. Thus, lenalidomide enhances the NK-cell armof 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-CD20monoclonal antibody (mAb) widely used to treat B-cellmalignancies.This supports combineduse 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 tobe penetrable to vesicles containingIFN-g.NKcells fromMMpatients also responded to lenalidomide in thisway.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.