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 (T-Regs), 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 T-Reg cell generation. Lenalidomide pre-treatment of MM cell lines reduced T-Reg generation and the concomitant T-Reg:T-Eff (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 T-Reg cell apoptosis without impacting on T-Eff cell survival. Combined lenalidomide and dexamethasone significantly reduced both T-Reg induction and the T-Reg:T-Eff cell ratio. In vivo, serial analysis of the T-Reg:T-Eff 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. (C) 2015 Elsevier Inc. All rights reserved.