Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer
Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer
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DOI：
10.3390/cancers11060874
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发表时间：
2019-06
期刊：
影响因子：
5.2
通讯作者：
Jiangang Zhao;H. Schlößer;Zhefang Wang;J. Qin;Jiahui Li;F. Popp;M. Popp;H. Alakus;S. Chon;H. Hansen;W. Neiss;K. Jauch;C. Bruns;Yue Zhao
中科院分区：
文献类型：
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作者：
Jiangang Zhao;H. Schlößer;Zhefang Wang;J. Qin;Jiahui Li;F. Popp;M. Popp;H. Alakus;S. Chon;H. Hansen;W. Neiss;K. Jauch;C. Bruns;Yue Zhao
胰腺导管腺癌（Pancreatic ductal adenocarcinoma，PDAC）是最致命的恶性肿瘤之一。肿瘤来源的细胞外囊泡（EV）诱导转移前小生境形成以促进转移。我们通过超离心从高转移性胰腺癌细胞系和患者来源的原发性癌细胞中分离EV。通过质谱分析EV的蛋白质含量。通过流式细胞术研究PDAC衍生的EV对自然杀伤（NK）细胞的影响。ELISA法检测血清TGF-β1水平。我们发现整合素在PDAC衍生的EV中富集。与EV共培养后，NK细胞中NKG 2D、CD 107 a、TNF-α和INF-γ的表达显著下调。NK细胞还表现出CD 71和CD 98水平降低，以及葡萄糖摄取能力受损。此外，NK细胞对胰腺癌干细胞的细胞毒性减弱。此外，PDAC衍生的EV诱导NK细胞中Smad 2/3的磷酸化。PDAC患者血清EVs TGF-β1水平明显升高。我们的研究结果强调了PDAC衍生EV的免疫抑制作用，并为我们理解PDAC中转移前生态位形成的NK细胞功能障碍提供了新的见解。
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of EVs was analyzed by mass spectrometry. The effects of PDAC-derived EVs on natural kill (NK) cells were investigated by flow cytometry. The serum EVs’ TGF-β1 levels were quantified by ELISA. We found that integrins were enriched in PDAC-derived EVs. The expression of NKG2D, CD107a, TNF-α, and INF-γ in NK cells was significantly downregulated after co-culture with EVs. NK cells also exhibited decreased levels of CD71 and CD98, as well as impaired glucose uptake ability. In addition, NK cell cytotoxicity against pancreatic cancer stem cells was attenuated. Moreover, PDAC-derived EVs induced the phosphorylation of Smad2/3 in NK cells. Serum EVs’ TGF-β1 was significantly increased in PDAC patients. Our findings emphasize the immunosuppressive role of PDAC-derived EVs and provide new insights into our understanding of NK cell dysfunction regarding pre-metastatic niche formation in PDAC.