Lenalidomide augments actin remodelling and lowers NK cell activation thresholds.

As multiple myeloma (MM) progresses, Natural Killer (NK) cell responses decline against malignant plasma cells. The immunomodulatory drug lenalidomide is widely used for the 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 EC50 for activation through CD16, and a 38% decrease in the EC50 for NKG2D-mediated activation, allowing NK cells to respond to lower doses of ligand. In addition, lenalidomide augments NK cell responses, causing a 2-fold increase in the proportion of primary NK cells producing 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 mAb widely used to treat B cell malignancies. This supports the combined use of lenalidomide and rituximab in a clinical setting. Finally, super-resolution 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 establishes that nanometre-scale rearrangements in cortical actin, a recently discovered step in immune synapse assembly, are a potential new target for therapeutic compounds.