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Lenalidomide and pomalidomide potently interfere with induction of myeloid‐derived suppressor cells in multiple myeloma
Author(s) -
KuwaharaOta Saeko,
Shimura Yuji,
Steinebach Christian,
Isa Reiko,
Yamaguchi Junko,
Nishiyama Daichi,
Fujibayashi Yuto,
TakimotoShimomura Tomoko,
Mizuno Yoshimi,
MatsumuraKimoto Yayoi,
Tsukamoto Taku,
Chinen Yoshiaki,
Kobayashi Tsutomu,
Horiike Shigeo,
Taniwaki Masafumi,
Gütschow Michael,
Kuroda Junya
Publication year - 2020
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.16881
Subject(s) - pomalidomide , irf8 , cereblon , cancer research , ccl5 , lenalidomide , peripheral blood mononuclear cell , multiple myeloma , immunology , chemokine , downregulation and upregulation , myeloid derived suppressor cell , biology , chemistry , medicine , transcription factor , t cell , suppressor , immune system , in vitro , gene , ubiquitin ligase , biochemistry , ubiquitin , cancer , il 2 receptor
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.