Anti-inflammatory modulation of human myeloid-derived dendritic cell subsets by lenalidomide

Yamamoto, Koji; Kitawaki, Toshio; Sugimoto, Naoshi; Fujita, Haruyuki; Kawase, Yumi; Takaori‐Kondo, Akifumi; Kadowaki, Norimitsu

doi:10.1016/j.imlet.2019.05.012

Cited by 15 publications

(14 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, we conclude that LEN and POM have a unique molecular effect that prevents MDSC induction. IMiD compounds exert various immunomodulatory functions on immune cells, including cytotoxic T cells, Tregs, NK cells, and dendritic cells 32–38 . Our present results showed that LEN and POM inhibit production of CCL5 and MIF from myeloma cells, with the former largely dependent on CRBN and the latter occurring mostly independent of CRBN.…”

Section: Discussionmentioning

confidence: 51%

Lenalidomide and pomalidomide potently interfere with induction of myeloid‐derived suppressor cells in multiple myeloma

et al. 2020

View full text Add to dashboard Cite

An increase in immunosuppressive myeloid-derived suppressor cells (MDSCs) is associated with disease progression and treatment resistance in multiple myeloma (MM). We investigated the mechanisms underlying MDSC induction, and sought to discover a strategy for prevention of MDSC induction in MM. Using a transwell co-culture system, four of nine examined human myeloma-derived cell lines (HMCLs) were potent in inducing monocytic (M)-MDSCs from normal peripheral blood mononuclear cells (PBMCs). As the results, we identified that secretion of CC motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF) by myeloma cells is a prerequisite for induction of MDSCs in MM. The immunomodulatory drug (IMiD) compounds, such as lenalidomide (LEN) and pomalidomide (POM), were identified as potent inhibitors of MDSC induction through bidirectional molecular effects of cereblon (CRBN)-dependent and-independent downregulation of CCL5 and MIF in myeloma cells; and downregulation of CC motif chemokine receptor 5, a receptor for CCL5, and induction of interferon regulatory factor 8, a critical transcription factor for monocytic differentiation, in PBMCs. In the present study of the molecular mechanisms underlying MDSC induction, we identified a novel effect of LEN and POM of inhibiting MDSC induction via overlapping regulatory effects in myeloma cells and normal PBMCs.

show abstract

Section: Discussionmentioning

confidence: 51%

Lenalidomide and pomalidomide potently interfere with induction of myeloid‐derived suppressor cells in multiple myeloma

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Furthermore, the present study also showed that both IMiDs suppressed the Th1-inducing capacity of DCs by downregulating STAT4, in line with the previous observations that LEN suppresses IL-12 and IL-23 production and enhances IL-10 production by mDCs in response to TLRligands. 22,23 Our findings also provide insight into the pathogenesis of IMiDinduced rashes. The incidence of all-grade LEN-associated rashes was 30.4% in our study.…”

Section: Discussionmentioning

confidence: 63%

“…There is evidence of immunomodulatory activity of IMiDs on mouse dendritic cells (DCs) 13,17 and a synergistic effect with DC vaccination in model of murine MM [18][19][20] or colon cancer, 21 however, only a few reports have examined its effects on human DC subsets. [22][23][24][25] DCs are capable of inducing Th1 or Th2 responses. Myeloid DCs (mDCs) are the major inducers of Th2 responses and play an important role in allergy by their dysregulated Th2-inducing function in diseases such as atopic dermatitis and asthma.…”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses

et al. 2020

View full text Add to dashboard Cite

Immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, are widely used treatments for multiple myeloma; however, they occasionally lead to episodes of itchy skin and rashes. Here, we analyzed the effects of IMiDs on human myeloid dendritic cells (mDCs) as major regulators of Th1 or Th2 responses and the role they play in allergy. We found that lenalidomide and pomalidomide used at clinical concentrations did not affect the survival or CD86 and OX40-ligand expression of blood mDCs in response to lipopolysaccharide (LPS) and thymic stromal lymphopoietin (TSLP) stimulation. Both lenalidomide and pomalidomide dose-dependently inhibited interleukin-12 (IL-12) and TNF production and STAT4 expression, and enhanced IL-10 production in response to LPS. When stimulated with TSLP, both IMiDs significantly enhanced CCL17 production and STAT6 and IRF4 expression and promoted memory Th2-cell responses. In 46 myeloma patients, serum CCL17 levels at the onset of lenalidomide-associated rash were significantly higher than those without rashes during lenalidomide treatment and those before treatment. Furthermore, serum CCL17 levels in patients who achieved a very good partial response (VGPR) were significantly higher compared with a less than VGPR during lenalidomide treatment. The median time to next treatment was significantly longer in lenalidomide-treated patients with rashes than those without. Collectively, IMiDs suppressed the Th1-inducing capacity of DCs, instead promoting a Th2 response. Thus, the lenalidomide-associated rashes might be a result of an allergic response driven by Th2-axis activation. Our findings suggest clinical efficacy and rashes as a side effect of IMiDs are inextricably linked through immunostimulation.

show abstract

“…Dendritic cells (DCs) are essential in the induction of appropriate immune responses as they link the adaptive and innate immune system (Carbone et al 1998 ), but, commonly used anti-myeloma drugs interfere with DCs. In detail, proteasome inhibitors and IMiDs suppress DC functionality (Nencioni et al 2006a , b ; Yamamoto et al 2019 ) as well as daratumumab depletes plasmacytoid DCs and modulates PD-L1 expression on antigen presenting cells (Stocker et al 2020 ), while it upregulates CD80 and CD86 on monocytes (Viola et al 2020 ). Given the increased infection rate observed in MM patients, we wondered whether elotuzumab modulates DC phenotype, function and their ability to induce T cell responses as well.…”

Section: To the Editormentioning

confidence: 99%

Elotuzumab spares dendritic cell integrity and functionality

Schlaweck

Strauss

Daecke

et al. 2021

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

show abstract

Anti-inflammatory modulation of human myeloid-derived dendritic cell subsets by lenalidomide

Cited by 15 publications

References 53 publications

Lenalidomide and pomalidomide potently interfere with induction of myeloid‐derived suppressor cells in multiple myeloma

Lenalidomide and pomalidomide potently interfere with induction of myeloid‐derived suppressor cells in multiple myeloma

Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses

Elotuzumab spares dendritic cell integrity and functionality

Contact Info

Product

Resources

About