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

// Brigitte Neuber 1, * , Jingying Dai 2, * , Wjahat A. Waraich 1 , Mohamed H.S. Awwad 1 , Melanie Engelhardt 1 , Michael Schmitt 1 , Sergej Medenhoff 1 , Mathias Witzens-Harig 1 , Anthony D. Ho 1 , Hartmut Goldschmidt 1, 3 and Michael Hundemer 1 1 Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany 2 Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China 3 National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany * These authors contributed equally to this work Correspondence to: Michael Hundemer, email: michael.hundemer@med.uni-heidelberg.de Keywords: lenalidomide, multiple myeloma, regulatory T-cells, IL-6 Received: January 17, 2017      Accepted: September 21, 2017      Published: October 05, 2017 ABSTRACT 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.