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- Title
Lenalidomide and pomalidomide potently interfere with induction of myeloid‐derived suppressor cells in multiple myeloma.
- Authors
Kuwahara‐Ota, Saeko; Shimura, Yuji; Steinebach, Christian; Isa, Reiko; Yamaguchi, Junko; Nishiyama, Daichi; Fujibayashi, Yuto; Takimoto‐Shimomura, Tomoko; Mizuno, Yoshimi; Matsumura‐Kimoto, Yayoi; Tsukamoto, Taku; Chinen, Yoshiaki; Kobayashi, Tsutomu; Horiike, Shigeo; Taniwaki, Masafumi; Gütschow, Michael; Kuroda, Junya
- Abstract
Summary: 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 C‐C 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 C‐C 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.
- Subjects
SUPPRESSOR cells; MULTIPLE myeloma; MACROPHAGE migration inhibitory factor; INTERFERON regulatory factors; CHEMOKINE receptors
- Publication
British Journal of Haematology, 2020, Vol 191, Issue 5, p784
- ISSN
0007-1048
- Publication type
Article
- DOI
10.1111/bjh.16881