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

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

doi:10.3390/cancers11060874

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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide [1].The majority of patients with pancreatic cancer are diagnosed at an advanced stage without the opportunity for curative surgery [2]
Results immunosuppressive factors and inhibit natural kill (NK) cell function, which contributes to pre-metastatic niche formation
Our findings suggest that pancreatic cancer-derived extracellular vesicles (EVs) induce a dysfunctional phenotype of NK cells, which contribute to an immunosuppressive microenvironment in the pre-metastatic niche

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide [1]. The majority of patients with pancreatic cancer are diagnosed at an advanced stage without the opportunity for curative surgery [2]. Cancers 2019, 11, 874 five-year overall survival for PDAC patients with localized disease is 34.3%. For those who present with distant metastases, this drops to merely 2.7%. These daunting statistics emphasize the importance of improving our understanding of the metastatic process to reduce the incidence of metastasis and develop effective therapeutic strategies for PDAC patients

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Discussion

Conclusion