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

• Lenalidomide reduces ICOS-L expression and TReg cell generation by myeloma cell lines.
• Dexamethasone induces TReg apoptosis without impairing effector T cells.
• Combined therapy reduces both TReg induction and the TReg:TEff ratio.
• The combination acts synergistically to reduce tumour-induced immune suppression.

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.