Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells
Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells
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DOI：
10.1182/blood-2013-02-482513
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发表时间：
2013-08-01
期刊：
影响因子：
20.3
通讯作者：
Cerwenka, Adelheid
中科院分区：
文献类型：
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作者：
Fiegler, Nathalie;Textor, Sonja;Cerwenka, Adelheid
天然杀伤（NK）细胞是对癌症的先天免疫反应期间的中心效应细胞。 NK细胞（例如NKP30）表达的天然细胞毒性受体参与转化细胞的识别。最近，在包括血液恶性肿瘤在内的各种肿瘤细胞的细胞表面上表达的新型B7家族成员B7-H6被确定为NKP30的激活配体。为了研究B7-H6的表达和调节，我们产生了单克隆抗体。我们的研究表明，在用泛或I类组蛋白脱乙酰基酶抑制剂（HDACI）以及小干扰RNA介导的类的RNA介导的类敲低后，B7-H6表面蛋白和Messenger RNA（mRNA）表达在各种肿瘤细胞系中的表达被下调。 I组蛋白脱乙酰基酶（HDAC）2或3。B7-H6下调与B7-H6报告基因的降低相关并减少B7-H6启动子的组蛋白乙酰化。在某些原发性淋巴瘤和肝细胞癌样品中，B7-H6 mRNA水平升高并与HDAC3表达相关。最后，通过HDACI在肿瘤细胞上下调B7-H6降低了NK细胞的NKP30依赖性效应子功能。因此，我们确定了一种新的机制，该机制控制了肿瘤细胞中B7-H6的表达，这对将免疫疗法与HDACI结合的潜在癌症具有影响。
Natural killer (NK) cells are central effector cells during innate immune responses against cancer. Natural cytotoxicity receptors expressed by NK cells such as NKp30 are involved in the recognition of transformed cells. Recently, the novel B7 family member B7-H6, which is expressed on the cell surface of various tumor cells including hematological malignancies, was identified as an activating ligand for NKp30. To investigate expression and regulation of B7-H6, we generated monoclonal antibodies. Our study reveals that B7-H6 surface protein and messenger RNA (mRNA) expression in various tumor cell lines was downregulated upon treatment with pan-or class I histone deacetylase inhibitors (HDACi) as well as after small interfering RNA-mediated knockdown of the class I histone deacetylases (HDAC) 2 or 3. B7-H6 downregulation was associated with decreased B7-H6 reporter activity and reduced histone acetylation at the B7-H6 promoter. In certain primary lymphoma and hepatocellular carcinoma samples, B7-H6 mRNA levels were elevated and correlated with HDAC3 expression. Finally, downregulation of B7-H6 on tumor cells by HDACi reduced NKp30-dependent effector functions of NK cells. Thus, we identified a novel mechanism that governs B7-H6 expression in tumor cells that has implications for potential cancer treatments combining immunotherapy with HDACi.