Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma.
Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma.
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肿瘤源性外泌体通过调节人鼻咽癌中富集的外泌体 microRNA 促进肿瘤进展和 T 细胞功能障碍
DOI：
10.18632/oncotarget.2118
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发表时间：
2014-07-30
期刊：
影响因子：
--
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Ye SB;Li ZL;Luo DH;Huang BJ;Chen YS;Zhang XS;Cui J;Zeng YX;Li J
肿瘤来源的外泌体含有生物活性蛋白质和信使和微小RNA（miRNA）。这些颗粒充当细胞间通讯的载体，并且是肿瘤发生和免疫逃逸的新兴介质。在这里，我们从鼻咽癌（NPC）患者的血清或TW 03细胞的上清液中分离出30-100 nm的外泌体。外周血exosome浓度升高与鼻咽癌患者淋巴结分期及预后有关（P < 0.05）。TW 03来源的外泌体通过抑制T细胞增殖和Th 1和Th 17分化以及促进NPC细胞体外诱导Treg而损害T细胞功能。这些结果与外泌体刺激的T细胞中ERK、STAT 1和STAT 3磷酸化的减少以及STAT 5磷酸化的增加有关。TW 03衍生的外泌体增加了促炎细胞因子IL-1β、IL-6和IL-10，但减少了IFNγ、IL-2和IL-17从CD 4+或CD 8 + T细胞的释放。此外，在来自患者血清或NPC细胞的外泌体中鉴定了五种常见的过表达的miRNA：hsa-miR-24- 3 p、hsa-miR-891 a、hsa-miR-106 a-5 p、hsa-miR-20 a-5 p和hsa-miR-1908。这些过表达的miRNA簇下调MARK 1信号通路，从而改变细胞增殖和分化。总体而言，这些观察结果揭示了肿瘤来源的外泌体的临床相关性和预后价值，并确定了由肿瘤来源的外泌体介导的调节NPC中T细胞功能的独特细胞间机制。
Tumor-derived exosomes contain biologically active proteins and messenger and microRNAs (miRNAs). These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape. Here, we isolated 30-100 nm exosomes from the serum of patients with nasopharyngeal carcinoma (NPC) or the supernatant of TW03 cells. Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients (P < 0.05). TW03-derived exosomes impaired T-cell function by inhibiting T-cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro. These results are associated with decreases in ERK, STAT1, and STAT3 phosphorylation and increases in STAT5 phosphorylation in exosome-stimulated T-cells. TW03-derived exosomes increased the proinflammatory cytokines IL-1β, IL-6, and IL-10 but decreased IFNγ, IL-2, and IL-17 release from CD4+ or CD8+ T-cells. Furthermore, five commonly over-expressed miRNAs were identified in the exosomes from patient sera or NPC cells: hsa-miR-24-3p, hsa-miR-891a, hsa-miR-106a-5p, hsa-miR-20a-5p, and hsa-miR-1908. These over-expressed miRNA clusters down-regulated the MARK1 signaling pathway to alter cell proliferation and differentiation. Overall, these observations reveal the clinical relevance and prognostic value of tumor-derived exosomes and identify a unique intercellular mechanism mediated by tumor-derived exosomes to modulate T-cell function in NPC.