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

Brigitte Neuber,Mathias Witzens-Harig,Sergej Medenhoff,Mohamed H.S Awwad,Wjahat A Waraich,Michael Hundemer,Melanie Engelhardt,Hartmut Goldschmidt,Jingying Dai,Anthony D Ho,Michael Schmitt

doi:10.18632/oncotarget.21516

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.

Highlights

In addition to the cytotoxic impact of lenalidomide on malignant plasma cells, its immunomodulatory capacity is well described in patients with multiple myeloma (MM)
We used dendritic cells (DC) to generate antigenspecific T-cells, and those DC might be the source of IL-10 in our model, explaining the inhibitory capacity of the CD8+CD28– T-cells in healthy donors (HDs) [33]
We found that lenalidomide dramatically decreases the amount of IL-6 in our coculture system and because we showed that the CD8+CD28– T-cells are not the main source of IL-6 in this model, the CD8+CD28– regulatory T-cells seem to trigger the secretion of IL-6 by mononuclear cells (MNC)

Summary

Introduction

In addition to the cytotoxic impact of lenalidomide on malignant plasma cells, its immunomodulatory capacity is well described in patients with multiple myeloma (MM). Other authors have found a CD8+CD28– T-cell induced imbalance in the production of Th1 and Th2 cytokines [17]. These CD8+CD28– regulatory T-cells were increased in various types of cancer and were defective in autoimmune diseases [14, 18,19,20,21,22]. Regarding the modulation of the CD8+CD28– regulatory T-cells, recent data have suggested that cyclophosphamide attenuates the immunosuppression of CD8+CD28– T-cell analogs compared with its impact on CD4+CD25+ regulatory T-cells [23,24,25,26]

Methods

Results

Conclusion