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

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          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.

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          Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.

          S. Bauer, V Groh, J. Wu … (1999)
          Stress-inducible MICA, a distant homolog of major histocompatibility complex (MHC) class I, functions as an antigen for gammadelta T cells and is frequently expressed in epithelial tumors. A receptor for MICA was detected on most gammadelta T cells, CD8+ alphabeta T cells, and natural killer (NK) cells and was identified as NKG2D. Effector cells from all these subsets could be stimulated by ligation of NKG2D. Engagement of NKG2D activated cytolytic responses of gammadelta T cells and NK cells against transfectants and epithelial tumor cells expressing MICA. These results define an activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses.
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            Every step of the way: integrins in cancer progression and metastasis

            Johanna Ivaska, Hellyeh Hamidi (2018)
            Cell adhesion to the extracellular matrix is fundamental to tissue integrity and human health. Integrins are the main cellular adhesion receptors that through multifaceted roles as signalling molecules, mechanotransducers and key components of the cell migration machinery are implicated in nearly every step of cancer progression from primary tumour development to metastasis. Altered integrin expression is frequently detected in tumours, where integrins have roles in supporting oncogenic growth factor receptor (GFR) signalling and GFR-dependent cancer cell migration and invasion. In addition, integrins determine colonization of metastatic sites and facilitate anchorage-independent survival of circulating tumour cells. Investigations describing integrin engagement with a growing number of versatile cell surface molecules, including channels, receptors and secreted proteins, continue to lead to the identification of novel tumour-promoting pathways. Integrin-mediated sensing, stiffening and remodelling of the tumour stroma are key steps in cancer progression supporting invasion, acquisition of cancer stem cell characteristics and drug resistance. Given the complexity of integrins and their adaptable and sometimes antagonistic roles in cancer cells and the tumour microenvironment, therapeutic targeting of these receptors has been a challenge. However, novel approaches to target integrins and antagonism of specific integrin subunits in stringently stratified patient cohorts are emerging as potential ways forward.
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              Control of Metastasis by NK Cells.

              Alejandro López-Soto, Segundo Jaime González, Lorenzo Galluzzi … (2017)
              The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancers (Basel)
                Journal ID (iso-abbrev): Cancers (Basel)
                Journal ID (publisher-id): cancers
                Title: Cancers
                Publisher: MDPI
                ISSN (Electronic): 2072-6694
                Publication date (Electronic): 22 June 2019
                Publication date Collection: June 2019
                Volume: 11
                Issue: 6
                Electronic Location Identifier: 874
                Affiliations
                [1 ]Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany; jiangang.zhao@ 123456uk-koeln.de (J.Z.); hans.schloesser@ 123456uk-koeln.de (H.A.S.); zhefang.wang@ 123456uk-koeln.de (Z.W.); jie.qin@ 123456uk-koeln.de (J.Q.); jiahui.li@ 123456uk-koeln.de (J.L.); felix.popp@ 123456uk-koeln.de (F.P.); marie.popp@ 123456uk-koeln.de (M.C.P.); hakan.alakus@ 123456uk-koeln.de (H.A.); seung-hun.chon@ 123456uk-koeln.de (S.-H.C.); christiane.bruns@ 123456uk-koeln.de (C.J.B.)
                [2 ]Department of General, Visceral und Vascular Surgery, Ludwig-Maximilian-University (LMU), 81377 Munich, Germany; Karl-Walter.Jauch@ 123456med.uni-muenchen.de
                [3 ]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; hinrich-peter.hansen@ 123456uk-koeln.de
                [4 ]Department of Anatomy I, Medical Faculty, University of Cologne, 50937 Cologne, Germany; wolfram.neiss@ 123456uk-koeln.de
                [5 ]Department of General, Visceral und Vascular Surgery, Otto von Guericke University, 39120 Magdeburg, Germany
                Author notes
                [* ]Correspondence: yue.zhao@ 123456uk-koeln.de ; Tel.: +49-221-4783-0601
                Author information
                https://orcid.org/0000-0002-8923-6428
                https://orcid.org/0000-0002-6790-3402
                Article
                Publisher ID: cancers-11-00874
                DOI: 10.3390/cancers11060874
                PMC ID: 6628179
                PubMed ID: 31234517
                SO-VID: 6682e5eb-f1e2-4eee-8ad7-cca2b73cb27a
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 07 June 2019
                Date accepted : 19 June 2019
                Categories
                Subject: Article

                Keywords: extracellular vesicles,nk cells,pancreatic cancer,pre-metastatic niche
                Data availability:
                Keywords: extracellular vesicles, nk cells, pancreatic cancer, pre-metastatic niche

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