The immunomodulatory drug lenalidomide augments NK cell IFN-γ secretion and lowers the threshold for NK cell activation (INC6P.351)

Abstract The immunomodulatory drug lenalidomide is widely used for the treatment of multiple myeloma. NK cells can kill tumour cells in early stage myeloma but there is a decline in NK cell cytotoxicity as the disease progresses. Previous studies have shown that lenalidomide increases antibody-dependent cellular cytotoxicity, yet little is known about its effects on cytokine secretion. Here, we show that lenalidomide increases IFN-γ secretion from primary human NK cells stimulated by NK-sensitive target cells. Moreover, after ligation of NK activating receptors CD16 and NKG2D, lenalidomide caused a 2-fold increase in the proportion of primary NK cells producing IFN-γ, and a 10-fold increase in the amount of IFN-γ produced per cell. This implies that lenalidomide acts downstream from early membrane-proximal signalling, which is distinct for these two receptors. In addition, lenalidomide-treated NK cells displayed a 2-fold decrease in the amount of ligand required to reach 50% of maximal activation, establishing that lenalidomide lowers the threshold for NK cell activation. Finally, using super resolution microscopy, we found that lenalidomide treatment increases the periodicity of the actin meshwork at the immune synapse during cytokine secretion, a cytoskeletal rearrangement likely to be important for its mechanism of action. Taken together, these results establish that lenalidomide influences cytokine secretion and lowers the threshold for NK cell activation.