The Proangiogenic Phenotype of Natural Killer Cells in Patients with Non-Small Cell Lung Cancer
The Proangiogenic Phenotype of Natural Killer Cells in Patients with Non-Small Cell Lung Cancer
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DOI：
10.1593/neo.121758
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发表时间：
2013-02-01
期刊：
影响因子：
4.8
通讯作者：
Noonan, Douglas M.
中科院分区：
文献类型：
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作者：
Bruno, Antonino;Focaccetti, Chiara;Noonan, Douglas M.
肿瘤微环境可使先天免疫细胞分化为促血管生成表型。蜕膜自然杀伤细胞（dNK）表现出血管生成表型，但NK先天淋巴样细胞在肿瘤血管生成中的作用仍有待明确。我们使用流式细胞术和功能分析研究了手术切除的非小细胞肺癌（NSCLC）患者和对照组的NK细胞。非小细胞肺癌患者的CD56(+)CD16(-) NK亚群代表肿瘤中的主要NK亚群和邻近肺和外周血中的次要NK亚群，与血管内皮生长因子（VEGF）、胎盘生长因子（PIGF）和白细胞介素-8 (IL-8)/CXCL8的产生有关。鳞状细胞癌（SCC）亚型患者的外周血CD56(+)CD16(-) NK细胞与腺癌（AdC）患者和对照组相比，VEGF和PlGF的产生更高。与对照组相比，SCC和AdC的IL-8产量均较高。来源于非小细胞肺癌CD56(+)CD16(-) NK细胞的上清液在体外诱导内皮细胞趋化和毛细血管样结构的形成，在SCC患者中尤其明显，而在对照组中没有。最后，暴露于转化生长因子- β (1) （TGF β(1)，一种与dNK极化相关的细胞因子）中，健康受试者外周血CD56(+)CD16(-) NK细胞中的VEGF和PlGF上调。我们的数据表明，非小细胞肺癌中的NK细胞具有促血管生成细胞的作用，特别是在SCC中，部分由TGF β介导(1)。
The tumor microenvironment can polarize innate immune cells to a proangiogenic phenotype. Decidual natural killer (dNK) cells show an angiogenic phenotype, yet the role for NK innate lymphoid cells in tumor angiogenesis remains to be defined. We investigated NK cells from patients with surgically resected non-small cell lung cancer (NSCLC) and controls using flow cytometric and functional analyses. The CD56(+)CD16(-) NK subset in NSCLC patients, which represents the predominant NK subset in tumors and a minor subset in adjacent lung and peripheral blood, was associated with vascular endothelial growth factor (VEGF), placental growth factor (PIGF), and interleukin-8 (IL-8)/CXCL8 production. Peripheral blood CD56(+)CD16(-) NK cells from patients with the squamous cell carcinoma (SCC) subtype showed higher VEGF and PlGF production compared to those from patients with adenocarcinoma (AdC) and controls. Higher IL-8 production was found for both SCC and AdC compared to controls. Supernatants derived from NSCLC CD56(+)CD16(-) NK cells induced endothelial cell chemotaxis and formation of capillary-like structures in vitro, particularly evident in SCC patients and absent from controls. Finally, exposure to transforming growth factor-beta(1) (TGF beta(1)), a cytokine associated with dNK polarization, upregulated VEGF and PlGF in peripheral blood CD56(+)CD16(-) NK cells from healthy subjects. Our data suggest that NK cells in NSCLC act as proangiogenic cells, particularly evident for SCC and in part mediated by TGF beta(1).