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

Abstract Multiple myeloma (MM) produces significant cellular and humoral immune defects. We have previously reported that MM induces CD4 + CD25 + FoxP 3 + 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.