Optimal selection of natural killer cells to kill myeloma: the role of HLA-E and NKG2A.
Optimal selection of natural killer cells to kill myeloma: the role of HLA-E and NKG2A.
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DOI：
10.1007/s00262-015-1694-4
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Wieten L
中科院分区：
文献类型：
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作者：
Sarkar S;van Gelder M;Noort W;Xu Y;Rouschop KM;Groen R;Schouten HC;Tilanus MG;Germeraad WT;Martens AC;Bos GM;Wieten L
同种异体自然杀伤（NK）细胞免疫治疗为多发性骨髓瘤患者提供了治疗前景。在这里，我们旨在通过评估hla - I类和HLA-E对NK抗骨髓瘤反应性的相关性来改进NK细胞治疗。我们发现hla - I类在患者源性骨髓瘤细胞表面和骨髓瘤细胞系上强烈表达。HLA-E在原发性骨髓瘤细胞中高表达，但在细胞系中仅少量表达。在rag2 - / - γ - c - / -小鼠体内（骨髓）生长后，体外观察到U266细胞上hla - low的表达强烈上调，表明体外HLA-E水平不能预测体内情况。同时分析抑制受体（KIR2DL1、KIR2DL2/3、KIR3DL1和NKG2A）和骨髓瘤细胞共培养的NK细胞脱粒结果显示，与kir配体不匹配的NK细胞比匹配的NK细胞脱粒更多，HLA-E消除了NKG2A+亚群的脱粒。白细胞介素2激活的NK细胞和低氧水平（0.6%）模拟骨髓缺氧壁龛（骨髓瘤细胞优先居住的地方）也观察到hla - I类和HLA-E的抑制作用。我们的研究表明，nkg2a阴性、kir配体错配的NK细胞是临床应用中最有效的亚群。我们设想大量输注该亚类将提高临床疗效。本文的在线版本（doi:10.1007/s00262-015-1694-4）包含补充材料，仅供授权用户使用。
Immunotherapy with allogeneic natural killer (NK) cells offers therapeutic perspectives for multiple myeloma patients. Here, we aimed to refine NK cell therapy by evaluation of the relevance of HLA-class I and HLA-E for NK anti-myeloma reactivity. We show that HLA-class I was strongly expressed on the surface of patient-derived myeloma cells and on myeloma cell lines. HLA-E was highly expressed by primary myeloma cells but only marginally by cell lines. HLA-Elow expression on U266 cells observed in vitro was strongly upregulated after in vivo (bone marrow) growth in RAG-2−/−γc−/− mice, suggesting that in vitro HLA-E levels poorly predict the in vivo situation. Concurrent analysis of inhibitory receptors (KIR2DL1, KIR2DL2/3, KIR3DL1 and NKG2A) and NK cell degranulation upon co-culture with myeloma cells revealed that KIR–ligand-mismatched NK cells degranulate more than matched subsets and that HLA-E abrogates degranulation of NKG2A+ subsets. Inhibition by HLA-class I and HLA-E was also observed with IL-2-activated NK cells and at low oxygen levels (0.6 %) mimicking hypoxic bone marrow niches where myeloma cells preferentially reside. Our study demonstrates that NKG2A-negative, KIR–ligand-mismatched NK cells are the most potent subset for clinical application. We envision that infusion of high numbers of this subclass will enhance clinical efficacy. The online version of this article (doi:10.1007/s00262-015-1694-4) contains supplementary material, which is available to authorized users.