Soluble SLAMF7 promotes the growth of myeloma cells via homophilic interaction with surface SLAMF7
Soluble SLAMF7 promotes the growth of myeloma cells via homophilic interaction with surface SLAMF7
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DOI：
10.1038/s41375-019-0525-6
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发表时间：
2020-01-01
期刊：
影响因子：
11.4
通讯作者：
Furukawa, Yusuke
中科院分区：
文献类型：
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作者：
Kikuchi, Jiro;Hori, Mitsuo;Furukawa, Yusuke
SLAMF7 主要在多发性骨髓瘤 (MM) 细胞上表达，被认为是免疫治疗方法的理想靶标。事实上，elotuzumab（一种抗 SLAMF7 抗体）与免疫调节药物联合用于治疗 MM。 SLAMF7 通过未知机制被裂解，并仅在 MM 患者的血清中检测为可溶形式 (sSLAMF7)；然而，人们对 sSLAMF7 在 MM 生物学中的作用知之甚少。在这项研究中，我们发现 sSLAMF7 通过与表面 SLAMF7 的同源相互作用以及随后激活 SHP-2 和 ERK 信号通路来增强 MM 细胞的生长。 Elotuzumab 在体外和体内均抑制 sSLAMF7 诱导的 MM 细胞生长。启动子分析确定 IKZF1 (Ikaros) 是 SLAMF7 基因的关键转录激活子。来那度胺及其类似物泊马度胺对 Ikaros 的药理学靶向下调了 SLAMF7 表达，并改善了 MM 细胞对 sSLAMF7 的反应。在小鼠异种移植模型中，Elotuzumab 与来那度胺联合使用可阻断 sSLAMF7 的生长促进功能。 sSLAMF7 的中和是 elotuzumab 的一种新型抗骨髓瘤机制，免疫调节药物可通过下调 MM 细胞表面 SLAMF7 的表达来增强该机制。这些发现可能为 MM 治疗中 Elotuzumab 的最佳使用提供重要信息。
SLAMF7 is expressed mainly on multiple myeloma (MM) cells and considered an ideal target for immunotherapeutic approaches. Indeed, elotuzumab, an anti-SLAMF7 antibody, is used for the treatment of MM in combination with immunomodulatory drugs. SLAMF7 is cleaved via unknown mechanisms and detected as a soluble form (sSLAMF7) exclusively in the serum of MM patients; however, little is known about the role of sSLAMF7 in MM biology. In this study, we found that sSLAMF7 enhanced the growth of MM cells via homophilic interaction with surface SLAMF7 and subsequent activation of the SHP-2 and ERK signaling pathways. Elotuzumab suppressed sSLAMF7-induced MM cell growth both in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the SLAMF7 gene. Pharmacological targeting of Ikaros by lenalidomide and its analog pomalidomide downregulated SLAMF7 expression and ameliorated the response of MM cells to sSLAMF7. Elotuzumab blocked the growth-promoting function of sSLAMF7 when combined with lenalidomide in a murine xenograft model. Neutralization of sSLAMF7 is a novel antimyeloma mechanism of elotuzumab, which is enhanced by immunomodulatory drugs via downregulation of surface SLAMF7 expression on MM cells. These findings may provide important information for the optimal use of elotuzumab in MM treatment.