Lenalidomide enhances myeloma-specific T-cell responses<i>in vivo</i>and<i>in vitro</i>

Krämer, Isabelle; Engelhardt, Melanie; Fichtner, Sabrina; Neuber, Brigitte; Medenhoff, Sergej; Bertsch, Uta; Hillengaß, Jens; Raab, Marc S.; Hose, Dirk; Ho, Anthony D.; Goldschmidt, Hartmut; Hundemer, Michael

doi:10.1080/2162402x.2016.1139662

Cited by 29 publications

(25 citation statements)

References 35 publications

(35 reference statements)

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“…however, this has not yet been confirmed in vivo 14,15 . We found the highest expression of surface PD1 in lymphocytes from patients with active disease (Dx, PD), whereas optimal disease control (CR) almost normalized PD1 levels ( Figure 2A).…”

mentioning

confidence: 79%

Expression of programmed death-1 on lymphocytes in myeloma patients is lowered during lenalidomide maintenance

Danhof¹,

Schreder²,

Knop³

et al. 2017

Haematologica

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mentioning

confidence: 79%

Expression of programmed death-1 on lymphocytes in myeloma patients is lowered during lenalidomide maintenance

Danhof¹,

Schreder²,

Knop³

et al. 2017

Haematologica

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“…In contrast, two studies actually showed reduced numbers of Tregs in MGUS and MM patients [ 23 , 24 ]. In more advanced myeloma, lenalidomide has been shown to increase the number of circulating Treg [ 14 , 25 – 28 ]. We and others previously showed that Tregs from MM patients are endowed with a potent immune suppressive capacity [ 5 , 17 , 19 , 24 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Krämer et al compared the immune environment in MM patients treated with or without lenalidomide. They found increased frequencies of CD8 + T-cell responses for the MM-associated antigen HM1.24 in patients treated with lenalidomide compared to patients without lenalidomide treatment [ 14 ]. Upon PMA/ionomycin stimulation higher numbers of IFN-γ, TNF-α and IL-21 secreting T cells were detected in MM patients under lenalidomide maintenance treatment compared to MM patients that did not receive lenalidomide [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of lenalidomide maintenance on the immune environment of multiple myeloma patients with low tumor burden after autologous stem cell transplantation

et al. 2018

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Lenalidomide is a potent anti-myeloma drug with immunomodulatory properties. It is increasingly used in a low-dose maintenance setting to prolong remission duration after standard treatment. Data on the in vivo effects of lenalidomide are scarce and sometimes different from the well-described in vitro effects. We therefore evaluated the numerical, phenotypical and functional impact of lenalidomide maintenance on several immune cell types in a cohort of seventeen homogeneously treated myeloma patients achieving a low residual myeloma burden after a bortezomib based-induction followed by autologous stem cell transplantation. Lenalidomide maintenance: 1) increased the fraction of naïve CD8+ T cells and several memory T-cell subsets, 2) reduced the numbers of terminal effector CD8+ T cells, 3) resulted in a higher expression of co-stimulatory molecules on resting T cells and of the inhibitory checkpoint molecules LAG-3 on CD4+ T cells and TIM-3 on CD4+ and CD8+ T cells, 4) reduced the number of TIGIT+ CD8+ T cells, 5) increased the number of regulatory T cells with a phenotype associated with strong suppressive capacity. Purified CD8+ T cells showed increased and more polyfunctional recall viral responses. However, PBMC responses were not enhanced during lenalidomide maintenance and CD4+ T-cell responses specific for the myeloma-associated antigen MAGE-C1 even tended to become lower. We conclude that lenalidomide maintenance after autologous stem cell transplantation has complex pleotropic effects on the immune environment. Immune interventions such as anti-myeloma vaccination should include measures to tackle an expanded inhibitory Treg compartment.

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“…Immature DC were obtained by culturing plastic adherent PBMCs for 5 days with culture medium consisting of RPMI 1640, 2 mM L-glutamine, and penicillin/streptomycin, supplemented with 5% heat-inactivated human AB serum, 800 U/mL human granulocyte-macrophage colony-stimulation factor (GM-CSF; Bayer Healthcare, Seattle, WA, USA), and 500 U/mL human Interleukin-4 (IL-4; R&D systems, Abingdon, Oxon, United Kingdom). Thereafter, differentiation into mature DC was induced by adding 10 ng/mL tumor necrosis factor-α (TNF-α), 1 μg/mL prostaglandin E2 (both from Sigma-Aldrich, Deisenhofen, Germany), and 1000 U/mL IL-6 (R&D systems; Abingdon, Oxon, United Kingdom) for 2 days as previously published [ 47 ].…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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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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Lenalidomide enhances myeloma-specific T-cell responsesin vivoandin vitro

Cited by 29 publications

References 35 publications

Expression of programmed death-1 on lymphocytes in myeloma patients is lowered during lenalidomide maintenance

Expression of programmed death-1 on lymphocytes in myeloma patients is lowered during lenalidomide maintenance

Impact of lenalidomide maintenance on the immune environment of multiple myeloma patients with low tumor burden after autologous stem cell transplantation

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

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