Lenalidomide enhances the function of dendritic cells generated from patients with multiple myeloma

Vo, Manh-Cuong; Anh-NguyenThi, Truc; Lee, Hyunju; Nguyen-Pham, Thanh-Nhan; Lakshmi, Thangaraj Jaya; Jung, Sung-Hoon; Kim, Hyeoung-Joon; Lee, Je‐Jung

doi:10.1016/j.exphem.2016.11.004

Cited by 30 publications

(24 citation statements)

References 33 publications

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“…However, LEN effect on human DCs are still unclear. One study, recently published [ 18 ], reported that LEN (5 μg/ml ≈ 20 μM) enhanced the maturation of DCs generated from PB of MM patients and increased the ability to stimulate T cell proliferation in line with our results [ 18 ]. Particularly we found that LEN, at concentrations reached in vivo in MM patients treated with this drug 5–25 mg daily, [ 27 , 34 ] significantly increased the expression of DC maturation markers, HLA-DR, CD86 and CD209, that are involved in DC co-stimulatory function and trafficking, [ 35 – 37 ] both in BM and PB of MM patients.…”

Section: Discussionsupporting

confidence: 91%

“…Currently, few data are reported on the possible effects of LEN on dendritic cells (DCs) populations. [ 9 , 16 – 18 ] Interestingly, it has been shown that DCs from peripheral blood (PB) were functionally defective in MM patients, since they had decreased expression of maturation markers and antigen presentation capacity [ 19 , 20 ]. Nevertheless, it is not known which is the role of DCs in the anti-MM effect of LEN.…”

Section: Introductionmentioning

confidence: 99%

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Lenalidomide increases human dendritic cell maturation in multiple myeloma patients targeting monocyte differentiation and modulating mesenchymal stromal cell inhibitory properties

et al. 2017

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The use of Lenalidomide (LEN), to reverse tumor-mediated immune suppression and amplify multiple myeloma-specific immunity is currently being explored. Particularly, LEN effects on dendritic cells (DCs) are still unclear. In this study, we investigated the potential effect of LEN on DC differentiation and activity. DCs were differentiated either from CD14+ cells obtained from patients with multiple myeloma or from a human monocytic cell line.LEN, at the concentration range reached in vivo, significantly increased the median intensity expression of HLA-DR, CD86 and CD209 by DCs derived from both bone marrow and peripheral myeloma monocytes and enhanced the production of Interleukin-8, C-C motif chemokine ligand (CCL) 2, CCL5 and tumor necrosis factor-α. Consistently, LEN pre-treated DCs showed an increased ability to stimulate autologous CD3+ cell proliferation. LEN effect on dendritic differentiation was associated with the degradation of the Cereblon-related factors Ikaros and Aiolos. Moreover, we showed that LEN also blunted mesenchymal stromal cell inhibitory effect on dendritic differentiation, inhibiting Casein Kinase-1α levels. Finally, in vitro data were confirmed in ex vivo cultures obtained from relapsed myeloma patients treated with LEN, showing a significant increase of DC differentiation from peripheral blood monocytes.In conclusion, LEN increased the expression of mature dendritic markers both directly and indirectly and enhanced DC ability to stimulate T cell proliferation and to release chemokines. This suggests a new possible mechanism by which LEN could exert its anti-myeloma activity.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Lenalidomide increases human dendritic cell maturation in multiple myeloma patients targeting monocyte differentiation and modulating mesenchymal stromal cell inhibitory properties

et al. 2017

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“…A similar pattern was seen in healthy donor DCs exposed to lenalidomide. The reduction in IL-12 secretion contrasted with reports showing that lenalidomide does not compromise IL-12 production from monocyte-derived DCs (moDCs) stimulated with CD40L 38 , 39 . However, moDCs are not dependent on IKZF1 for development 40 and in vitro stimulation with CD40L triggers IL-12 production through the non-canonical, nuclear factor (NF)-κB (p52/p100) pathway.…”

Section: Discussioncontrasting

confidence: 89%

Ikaros family zinc finger 1 regulates dendritic cell development and function in humans

et al. 2018

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Ikaros family zinc finger 1 (IKZF1) is a haematopoietic transcription factor required for mammalian B-cell development. IKZF1 deficiency also reduces plasmacytoid dendritic cell (pDC) numbers in mice, but its effects on human DC development are unknown. Here we show that heterozygous mutation of IKZF1 in human decreases pDC numbers and expands conventional DC1 (cDC1). Lenalidomide, a drug that induces proteosomal degradation of IKZF1, also decreases pDC numbers in vivo, and reduces the ratio of pDC/cDC1 differentiated from progenitor cells in vitro in a dose-dependent manner. In addition, non-classical monocytes are reduced by IKZF1 deficiency in vivo. DC and monocytes from patients with IKZF1 deficiency or lenalidomide-treated cultures secrete less IFN-α, TNF and IL-12. These results indicate that human DC development and function are regulated by IKZF1, providing further insights into the consequences of IKZF1 mutation on immune function and the mechanism of immunomodulation by lenalidomide.

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“…DCs are the most potent antigen-presenting cells (APCs) that are capable of recognizing, processing and presenting tumor cells and thus play a central role in various immunotherapy protocols to generate cytotoxic T lymphocytes (CTLs) [7–15]. …”

Section: Introductionmentioning

confidence: 99%

Combination therapy with dendritic cells and lenalidomide is an effective approach to enhance antitumor immunity in a mouse colon cancer model

Nguyen-Pham

Lee

et al. 2017

Oncotarget

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In this study, we investigated efficacy of lenalidomide in combination with tumor antigen-loaded dendritic cells (DCs) in murine colon cancer model. MC-38 cell lines were injected subcutaneously to establish colon cancer-bearing mice. After tumor growth, lenalidomide (50 mg/kg/day) was injected intraperitoneally on 3 consecutive days in combination with tumor antigen-loaded DC vaccination on days 8, 12, 16, and 20. The tumor antigen-loaded DCs plus lenalidomide combination treatment exhibited a significant inhibition of tumor growth compared with the other groups. These effects were associated with a reduction in immune suppressor cells, such as myeloid-derived suppressor cells and regulatory T cells, with the induction of immune effector cells, such as natural killer cells, CD4+ T cells and CD8+ T cells in spleen, and with the activation of cytotoxic T lymphocytes and NK cells. This study suggests that a combination of tumor antigen-loaded DC vaccination and lenalidomide synergistically enhanced antitumor immune response in the murine colon cancer model, by inhibiting the generation of immune suppressive cells and recovery of effector cells, and demonstrated superior polarization of Th1/Th2 balance in favor of Th1 immune response. This combination approach with DCs and lenalidomide may provide a new therapeutic option to improve the treatment of colon cancer.

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Lenalidomide enhances the function of dendritic cells generated from patients with multiple myeloma

Cited by 30 publications

References 33 publications

Lenalidomide increases human dendritic cell maturation in multiple myeloma patients targeting monocyte differentiation and modulating mesenchymal stromal cell inhibitory properties

Lenalidomide increases human dendritic cell maturation in multiple myeloma patients targeting monocyte differentiation and modulating mesenchymal stromal cell inhibitory properties

Ikaros family zinc finger 1 regulates dendritic cell development and function in humans

Combination therapy with dendritic cells and lenalidomide is an effective approach to enhance antitumor immunity in a mouse colon cancer model

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