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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 th...

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Autores principales: Neuber, Brigitte, Dai, Jingying, Waraich, Wjahat A., Awwad, Mohamed H.S., Engelhardt, Melanie, Schmitt, Michael, Medenhoff, Sergej, Witzens-Harig, Mathias, Ho, Anthony D., Goldschmidt, Hartmut, Hundemer, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716723/
https://www.ncbi.nlm.nih.gov/pubmed/29228683
http://dx.doi.org/10.18632/oncotarget.21516
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author Neuber, Brigitte
Dai, Jingying
Waraich, Wjahat A.
Awwad, Mohamed H.S.
Engelhardt, Melanie
Schmitt, Michael
Medenhoff, Sergej
Witzens-Harig, Mathias
Ho, Anthony D.
Goldschmidt, Hartmut
Hundemer, Michael
author_facet Neuber, Brigitte
Dai, Jingying
Waraich, Wjahat A.
Awwad, Mohamed H.S.
Engelhardt, Melanie
Schmitt, Michael
Medenhoff, Sergej
Witzens-Harig, Mathias
Ho, Anthony D.
Goldschmidt, Hartmut
Hundemer, Michael
author_sort Neuber, Brigitte
collection PubMed
description 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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spelling pubmed-57167232017-12-08 Lenalidomide overcomes the immunosuppression of regulatory CD8(+)CD28(−) T-cells Neuber, Brigitte Dai, Jingying Waraich, Wjahat A. Awwad, Mohamed H.S. Engelhardt, Melanie Schmitt, Michael Medenhoff, Sergej Witzens-Harig, Mathias Ho, Anthony D. Goldschmidt, Hartmut Hundemer, Michael Oncotarget Research Paper 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. Impact Journals LLC 2017-10-05 /pmc/articles/PMC5716723/ /pubmed/29228683 http://dx.doi.org/10.18632/oncotarget.21516 Text en Copyright: © 2017 Neuber et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Neuber, Brigitte
Dai, Jingying
Waraich, Wjahat A.
Awwad, Mohamed H.S.
Engelhardt, Melanie
Schmitt, Michael
Medenhoff, Sergej
Witzens-Harig, Mathias
Ho, Anthony D.
Goldschmidt, Hartmut
Hundemer, Michael
Lenalidomide overcomes the immunosuppression of regulatory CD8(+)CD28(−) T-cells
title Lenalidomide overcomes the immunosuppression of regulatory CD8(+)CD28(−) T-cells
title_full Lenalidomide overcomes the immunosuppression of regulatory CD8(+)CD28(−) T-cells
title_fullStr Lenalidomide overcomes the immunosuppression of regulatory CD8(+)CD28(−) T-cells
title_full_unstemmed Lenalidomide overcomes the immunosuppression of regulatory CD8(+)CD28(−) T-cells
title_short Lenalidomide overcomes the immunosuppression of regulatory CD8(+)CD28(−) T-cells
title_sort lenalidomide overcomes the immunosuppression of regulatory cd8(+)cd28(−) t-cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716723/
https://www.ncbi.nlm.nih.gov/pubmed/29228683
http://dx.doi.org/10.18632/oncotarget.21516
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