Negative regulation of tumor-infiltrating NK cell in clear cell renal cell carcinoma patients through the exosomal pathway.
Negative regulation of tumor-infiltrating NK cell in clear cell renal cell carcinoma patients through the exosomal pathway.
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通过外泌体途径对透明细胞肾细胞癌患者肿瘤浸润 NK 细胞的负调控
DOI：
10.18632/oncotarget.16354
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发表时间：
2017-06-06
期刊：
影响因子：
--
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Xia Y;Zhang Q;Zhen Q;Zhao Y;Liu N;Li T;Hao Y;Zhang Y;Luo C;Wu X
自然杀伤细胞是肿瘤免疫的关键组成部分，其功能缺陷是肿瘤免疫逃逸的必要条件。肿瘤细胞源性外泌体的研究已经显示了其在肿瘤微环境中的生物学意义，但外泌体在肾透明细胞癌患者中调节自然杀伤细胞功能的潜在作用仍然未知。首先，我们精确地描述了肾透明细胞癌患者与健康对照组中自然杀伤细胞的表型和功能。与来自肿瘤边缘组织和非肿瘤组织的自然杀伤细胞相比，具有抑制表型的肿瘤浸润自然杀伤细胞表现出较差的细胞毒性能力和产生细胞因子的缺陷潜力。接下来，我们揭示了原发性肿瘤细胞以外泌体依赖性方式抑制自然杀伤细胞功能障碍。有趣的是，来自原发性肿瘤细胞的外泌体优先富集TGF-β 1，其充当自然杀伤细胞功能缺陷的重要介质。在体外培养的外来体诱导的自然杀伤细胞功能障碍介导的TGF-β/SMAD信号通路的激活，并通过敲低TGF-β废除。我们的数据表明，来自肾透明细胞癌的外泌体通过调节TGF-β/SMAD途径来逃避先天免疫监视，从而诱导自然杀伤细胞功能障碍。
Natural killer cells are the key components in tumor immunity and defects in function are necessary for tumor immune escape. Emerging studies on tumor cell-derived exosomes have shown the biological significance in tumor microenvironment, but the underlying role of exosomes in regulating natural killer cells functions in clear cell renal cell carcinoma patients remains unknown. Firstly, we precisely characterized the phenotype and function of natural killer cells in clear cell renal cell carcinoma patients vs healthy controls. With an inhibitory phenotype, tumor-infiltrating natural killer cells exhibited poor cytotoxic capacity and deficient potential to produce cytokines compared with natural killer cells from tumor margin tissue and non-tumor tissue. Next, we revealed that primary tumor cells trigged natural killer cell dysfunction in an exosome-dependent manner. Interestingly, exosomes from primary tumor cells were preferentially enriched with TGF-β1 which acted as important mediator of natural killer cell functional deficiency. In vitro culture of exosomes induced natural killer cell dysfunction mediated by activation of the TGF-β/SMAD signaling pathway, and abrogated by knockdown TGF-β. Our data indicate that exosomes from clear cell renal cell carcinoma induce natural killer cells dysfunction by regulating the TGF-β/SMAD pathway to evade innate immune surveillance.
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4.4
作者：
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作者：
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发表时间：
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期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
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