Downregulation of myeloma-induced ICOS-L and regulatory T cell generation by lenalidomide and dexamethasone therapy

Multiple myeloma (MM) produces significant cellular and humoral immune defects. We have previously reported that MM induces CD4(+)CD25(+)FoxP3(+) cells (TRegs), via tumour expression of the immune checkpoint regulator, ICOS-L. We sought to define what impact the immunomodulatory drug lenalidomide, alone or with dexamethasone, has on TReg cell generation. Lenalidomide pre-treatment of MM cell lines reduced TReg generation and the concomitant TReg:TEff (CD4(+)CD25(+)FoxP3(-): effector T cells) ratio, as a consequence of reduced ICOSL transcription. Dexamethasone did not affect surface ICOS-L expression but did induce TReg cell apoptosis without impacting on TEff cell survival. Combined lenalidomide and dexamethasone significantly reduced both TReg induction and the TReg:TEff cell ratio. In vivo, serial analysis of the TReg:TEff ratio in MM patients on lenalidomide-dexamethasone therapy revealed a progressive reduction towards age-matched control values, though not complete correction. Our data demonstrate for the first time immune synergism to explain the observed immune-modulation associated with lenalidomide-dexamethasone therapy.