Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma
Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma
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DOI：
10.1182/blood-2010-04-279893
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发表时间：
2010-10-28
期刊：
影响因子：
20.3
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
Goerguen, Guellue;Calabrese, Elisabetta;Anderson, Kenneth C.
骨髓（BM）微环境由细胞外基质和包括免疫细胞的细胞区室组成。多发性骨髓瘤（MM）细胞和BM辅助细胞相互作用通过细胞-细胞接触和细胞因子促进MM存活。免疫调节剂（IMiD）不仅靶向MM细胞，而且靶向MM细胞-免疫细胞相互作用和细胞因子信号传导。在这里，我们检查了IMiD对由效应细胞与MM细胞和BM基质细胞的相互作用触发的细胞因子信号传导的体外作用。IMiD降低了MM患者BM和PB免疫（CD 4 T、CD 8 T、自然杀伤T、自然杀伤）细胞中的白细胞介素-2、干扰素γ和IL-6调节因子细胞因子信号转导抑制因子（SOCS）1表达。此外，MM细胞与健康PBMC的共培养诱导效应细胞中的SOCS 1表达;相反，用IMiD处理下调SOCS 1表达。SOCS 1负调节IL-6信号传导，并通过MM细胞中的超甲基化沉默。为了确定效应细胞和MM细胞中的免疫细胞因子信号传导机制，我们接下来分析了免疫细胞与表观遗传修饰以重新表达SOCS 1的MM细胞的相互作用;与未修饰的MM细胞相比，IMiD诱导了针对重新表达SOCS 1的MM细胞的更有效的CTL应答。因此，这些数据表明，SOCS 1的调节可以增强MM中IMiD的免疫应答和功效。2010;116（17）：3227-3237）
The bone marrow (BM) microenvironment consists of extracellular-matrix and the cellular compartment including immune cells. Multiple myeloma (MM) cell and BM accessory cell interaction promotes MM survival via both cell-cell contact and cytokines. Immunomodulatory agents (IMiDs) target not only MM cells, but also MM cell-immune cell interactions and cytokine signaling. Here we examined the in vitro effects of IMiDs on cytokine signaling triggered by interaction of effector cells with MM cells and BM stroma cells. IMiDs diminished interleukin-2, interferon gamma, and IL-6 regulator suppressor of cytokine signaling (SOCS) 1 expression in immune (CD4T, CD8T, natural-killer T, natural-killer) cells from both BM and PB of MM patients. In addition, coculture of MM cells with healthy PBMCs induced SOCS1 expression in effector cells; conversely, treatment with IMiDs down-regulated the SOCS1 expression. SOCS1 negatively regulates IL-6 signaling and is silenced by hypermethylation in MM cells. To define the mechanism of inhibitory-cytokine signaling in effector cells and MM cells, we next analyzed the interaction of immune cells with MM cells that were epigenetically modified to re-express SOCS1; IMiDs induced more potent CTL responses against SOCS1 re-expressing-MM cells than unmodified MM cells. These data therefore demonstrate that modulation of SOCS1 may enhance immune response and efficacy of IMiDs in MM. (Blood. 2010;116(17):3227-3237)