Immune Cell Inhibition by SLAMF7 Is Mediated by a Mechanism Requiring Src Kinases, CD45, and SHIP-1 That Is Defective in Multiple Myeloma Cells
Immune Cell Inhibition by SLAMF7 Is Mediated by a Mechanism Requiring Src Kinases, CD45, and SHIP-1 That Is Defective in Multiple Myeloma Cells
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DOI：
10.1128/mcb.01107-14
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发表时间：
2015-01-01
影响因子：
5.3
通讯作者：
Veillette, Andre
中科院分区：
文献类型：
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作者：
Guo, Huaijian;Cruz-Munoz, Mario-Ernesto;Veillette, Andre
信号转导淋巴细胞激活分子F7(SLAMF7)是一种存在于免疫细胞上的受体，包括自然杀伤(NK)细胞。它也表达在多发性骨髓瘤(MM)细胞上。这导致了抗SLAMF7抗体elotuzumab的开发，该抗体显示出对MM的有效性。SLAMF7介导NK细胞的激活或抑制效应，取决于细胞是否表达适配器EAT-2。由于MM细胞缺乏EAT-2，我们阐明了SLAMF7在EAT-2阴性的NK细胞中的抑制效应，并测试了这些效应是否在MM细胞中被触发。SLAMF7对缺失EAT-2的NK细胞的抑制作用是由含有SH2结构域的肌醇磷酸酶1(SHIP-1)介导的，SHIP-1通过SLAMF7的酪氨酸261募集。SLAMF7与SHIP-1的偶联需要Src激酶，使SLAMF7磷酸化。虽然MM细胞缺乏EAT-2，但elotuzumab不能在这些细胞中诱导抑制信号。这至少部分是由于缺乏CD45，这是一种激活Src激酶所需的磷酸酶。CD45缺陷的NK细胞中也存在SLAMF7功能缺陷。因此，SLAMF7触发的抑制是通过一种机制介导的，该机制涉及到MM细胞中存在缺陷的Src激酶、CD45和SHIP-1。这一缺陷可能解释了为什么elotuzumab通过涉及NK细胞激活的间接机制来消除MM细胞。
Signaling lymphocytic activation molecule F7 (SLAMF7) is a receptor present on immune cells, including natural killer (NK) cells. It is also expressed on multiple myeloma (MM) cells. This led to development of an anti-SLAMF7 antibody, elotuzumab, showing efficacy against MM. SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express or do not express the adaptor EAT-2. Since MM cells lack EAT-2, we elucidated the inhibitory effectors of SLAMF7 in EAT-2-negative NK cells and tested whether these effectors were triggered in MM cells. SLAMF7-mediated inhibition in NK cells lacking EAT-2 was mediated by SH2 domain-containing inositol phosphatase 1 (SHIP-1), which was recruited via tyrosine 261 of SLAMF7. Coupling of SLAMF7 to SHIP-1 required Src kinases, which phosphorylated SLAMF7. Although MM cells lack EAT-2, elotuzumab did not induce inhibitory signals in these cells. This was at least partly due to a lack of CD45, a phosphatase required for Src kinase activation. A defect in SLAMF7 function was also observed in CD45-deficient NK cells. Hence, SLAMF7-triggered inhibition is mediated by a mechanism involving Src kinases, CD45, and SHIP-1 that is defective in MM cells. This defect might explain why elotuzumab eliminates MM cells by an indirect mechanism involving the activation of NK cells.