Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions
Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions
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CD48/2B4 相互作用介导单核细胞/巨噬细胞引起的肝细胞癌自然杀伤细胞功能障碍
DOI：
10.1002/hep.26192
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发表时间：
2013-03-01
期刊：
影响因子：
13.5
通讯作者：
Zheng, Limin
中科院分区：
文献类型：
--
作者：
Wu, Yan;Kuang, Dong-Ming;Zheng, Limin
自然杀伤（NK）细胞功能的缺陷是肿瘤免疫逃逸所必需的，但其在人类癌症中的潜在调控机制在很大程度上仍然未知。在这里，我们显示，在294例未经治疗的肝细胞癌（HCC）患者的NK细胞的详细研究中，功能性NK细胞在HCC组织中的积累可以预测患者生存率的提高。然而，在晚期HCC患者中，NK细胞数量显著减少，肿瘤坏死因子α（TNF-）和干扰素γ（IFN-）产生受损。肿瘤周围基质单核细胞/巨噬细胞的高度浸润与肿瘤内区域NK细胞功能活性受损呈正相关。进一步的动力学实验显示，在暴露于肿瘤来源的单核细胞后不久，NK细胞经历了快速、短暂的激活，但随后它们变得疲惫，并最终死亡。来自HCC组织的单核细胞强烈表达CD 48蛋白，而非来自非肿瘤性肝脏的单核细胞表达CD 48蛋白;通过阻断NK细胞上的CD 48受体2B 4，而不是通过阻断NKG 2D和NKp 30，这种单核细胞诱导的NK细胞功能障碍显著减弱。结论：这些数据表明，人类NK细胞受到不同类型免疫细胞之间微调的协同作用的调节，这可能反映了一种新的免疫逃逸机制，肿瘤通过这种机制在不同的肿瘤微环境中动态调节其功能。（肝脏学2013）
Defects in natural killer (NK) cell functions are necessary for tumor immune escape, but their underlying regulatory mechanisms in human cancers remain largely unknown. Here we show, in detailed studies of NK cells in 294 untreated patients with hepatocellular carcinoma (HCC), that accumulation of functional NK cells in HCC tissues could predict improved survival of patients. However, in patients with advanced-stage HCC, NK cells were significantly decreased in number with impaired tumor necrosis factor alpha (TNF-) and interferon-gamma (IFN-) production. High infiltration of peritumoral stroma monocytes/macrophages was positively correlated with impaired functional activities of NK cells in intratumoral areas. Further kinetic experiments revealed that soon after exposure to tumor-derived monocytes, NK cells underwent a rapid, transient activation, but then they became exhausted, and eventually died. The monocytes from HCC tissues, but not from nontumoral liver, strongly express CD48 proteins; and such monocyte-induced NK cell dysfunction was markedly attenuated by blocking CD48 receptor 2B4 on NK cells, but not by blockade of NKG2D and NKp30. Conclusion: These data reveal that human NK cells are regulated by a fine-tuned collaborative action between different types of immune cells, which may reflect a novel immune-escape mechanism by which tumors dynamically regulate their functions at distinct tumor microenvironments. (HEPATOLOGY 2013)