Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer

Jiangang Zhao; Hans  A. Schlößer; Zhefang Wang; Jie Qin; Jiahui Li; Felix Popp; Marie  Christine Popp; Hakan Alakus; Seung-Hun Chon; Hinrich  P. Hansen; Wolfram  F. Neiss; Karl-Walter Jauch; Christiane  J. Bruns; Yue Zhao

doi:10.3390/cancers11060874

Cancers (Jun 2019)

Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer

Jiangang Zhao,
Hans A. Schlößer,
Zhefang Wang,
Jie Qin,
Jiahui Li,
Felix Popp,
Marie Christine Popp,
Hakan Alakus,
Seung-Hun Chon,
Hinrich P. Hansen,
Wolfram F. Neiss,
Karl-Walter Jauch,
Christiane J. Bruns,
Yue Zhao

Affiliations

Jiangang Zhao: Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany
Hans A. Schlößer: Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany
Zhefang Wang: Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany
Jie Qin: Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany
Jiahui Li: Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany
Felix Popp: Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany
Marie Christine Popp: Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany
Hakan Alakus: Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany
Seung-Hun Chon: Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany
Hinrich P. Hansen: Department I of Internal Medicine, University Hospital of Cologne, Center for Integrated Oncology Cologne-Bonn, CECAD Center of Excellence on “Cellular Stress Responses in Aging-Associated Diseases”, Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
Wolfram F. Neiss: Department of Anatomy I, Medical Faculty, University of Cologne, 50937 Cologne, Germany
Karl-Walter Jauch: Department of General, Visceral und Vascular Surgery, Ludwig-Maximilian-University (LMU), 81377 Munich, Germany
Christiane J. Bruns: Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany
Yue Zhao: Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany

DOI: https://doi.org/10.3390/cancers11060874
Journal volume & issue: Vol. 11, no. 6
p. 874

Abstract

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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.

Published in Cancers

ISSN: 2072-6694 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.mdpi.com/journal/cancers/

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