Lenalidomide overcomes the immunosuppression of regulatory CD8⁺CD28^- T-cells

Although lenalidomide and pomalidomide are well-established treatment options in patients with multiple myeloma, their immune-modulating effects are not fully understood. While CD8⁺CD28^- regulatory T-cells in patients with hematologic disorders display a known immune-escape mechanism, we show that lenalidomide can overcome the immunosuppressive impact of CD8⁺CD28^- T-cells. We analyzed in vitro the antigen-specific T-cell responses of healthy donors and patients with multiple myeloma with or without the addition of autologous CD8⁺CD28^- T-cells in the absence and presence of lenalidomide. We found that lenalidomide enhances the antigen-specific secretion of IFN-γ and Granzyme B despite the addition of CD8⁺CD28^- T-cells. Furthermore, we showed that lenalidomide inhibits the IL-6 secretion of mononuclear cells, triggered by CD8⁺CD28^- T-cells. The addition of IL-6 counteracts the action of lenalidomide based stimulation of IFN-γ secretion and induction of T-cell maturation but not the secretion of Granzyme B. Surprisingly, pomalidomide failed to induce IL-6 suppression and displayed immunostimulating effects only after a prolonged incubation time. Analysis of the IL-6 modulating cereblon-binding protein KPNA2 showed the similar degradation capacity of lenalidomide and pomalidomide without explaining the divergent effects. In conclusion, we showed that IL-6 and lenalidomide, but not pomalidomide, are opponents in a myeloma-antigen specific T-cell model.