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
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DOI：
10.1111/bjh.16881
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发表时间：
2020-06-19
影响因子：
6.5
通讯作者：
Kuroda, Junya
中科院分区：
文献类型：
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作者：
Kuwahara-Ota, Saeko;Shimura, Yuji;Kuroda, Junya
免疫抑制性骨髓源性抑制细胞 (MDSC) 的增加与多发性骨髓瘤 (MM) 的疾病进展和治疗耐药相关。我们研究了 MDSC 诱导的机制，并试图发现预防 MM 中 MDSC 诱导的策略。使用 Transwell 共培养系统，检测到的 9 种人骨髓瘤衍生细胞系 (HMCL) 中的 4 种能够从正常外周血单核细胞 (PBMC) 中有效诱导单核细胞 (M)-MDSC。结果，我们发现骨髓瘤细胞分泌 C-C 基序趋化因子配体 5 (CCL5) 和巨噬细胞迁移抑制因子 (MIF) 是 MM 中诱导 MDSC 的先决条件。免疫调节药物 (IMiD) 化合物，如来那度胺 (LEN) 和泊马度胺 (POM)，通过 cereblon (CRBN) 依赖性和独立性下调骨髓瘤细胞中 CCL5 和 MIF 的双向分子效应，被确定为 MDSC 诱导的有效抑制剂； PBMC 中 C-C 基序趋化因子受体 5（CCL5 的一种受体）的下调，以及干扰素调节因子 8（单核细胞分化的关键转录因子）的诱导。在目前 MDSC 诱导分子机制的研究中，我们发现了 LEN 和 POM 通过在骨髓瘤细胞和正常 PBMC 中重叠的调节作用来抑制 MDSC 诱导的新作用。
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 inductionviaoverlapping regulatory effects in myeloma cells and normal PBMCs.