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- Title
Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer.
- Authors
Zhao, Jiangang; Schlößer, Hans A.; Wang, Zhefang; Qin, Jie; Li, Jiahui; Popp, Felix; Popp, Marie Christine; Alakus, Hakan; Chon, Seung-Hun; Hansen, Hinrich P.; Neiss, Wolfram F.; Jauch, Karl-Walter; Bruns, Christiane J.; Zhao, Yue
- Abstract
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.
- Subjects
GLUCOSE metabolism; ADENOCARCINOMA; ANIMAL experimentation; CELL death; CELL lines; CELL receptors; ENZYME-linked immunosorbent assay; EXTRACELLULAR space; FLOW cytometry; GENE expression; IMMUNOSUPPRESSION; KILLER cells; METASTASIS; MICE; PANCREATIC tumors; PHOSPHORYLATION; STEM cells; TRANSFORMING growth factors-beta; BLOOD
- Publication
Cancers, 2019, Vol 11, Issue 6, p874
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers11060874