Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:98200-98214. https://doi.org/10.18632/oncotarget.21516

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Abstract

Brigitte Neuber1,*, Jingying Dai2,*, Wjahat A. Waraich1, Mohamed H.S. Awwad1, Melanie Engelhardt1, Michael Schmitt1, Sergej Medenhoff1, Mathias Witzens-Harig1, Anthony D. Ho1, Hartmut Goldschmidt1,3 and Michael Hundemer1

1Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

2Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China

3National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany

*These authors contributed equally to this work

Correspondence to:

Michael Hundemer, email: [email protected]

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.


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