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

Cancers - Tập 11 Số 6 - Trang 874
Jiangang Zhao1, Hans Schlößer2, Zhefang Wang2, Jie Qin2, Jiahui Li2, Felix Popp2, Marie Popp2, Hakan Alakus2, Seung‐Hun Chon2, Hinrich P. Hansen3, Wolfram F. Neiss4, Karl‐Walter Jauch5, Christiane J. Bruns2, Yue Zhao6
1Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany; Department of General, Visceral und Vascular Surgery, Ludwig-Maximilian-University (LMU), 81377 Munich, Germany
2Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
3Department 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
4Department of Anatomy I, Medical Faculty, University of Cologne, 50937 Cologne, Germany
5Department of General, Visceral und Vascular Surgery, Ludwig-Maximilian-University (LMU), 81377 Munich, Germany
6Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany; Department of General, Visceral und Vascular Surgery, Otto von Guericke University, 39120 Magdeburg, Germany

Tóm tắt

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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Tài liệu tham khảo

Kamisawa, 2016, Pancreatic cancer, Lancet, 388, 73, 10.1016/S0140-6736(16)00141-0

Kommalapati, A., Tella, S.H., and Goyal, G. (2018). Contemporary Management of Localized Resectable Pancreatic Cancer. Cancers (Basel), 10.

Suker, 2016, FOLFIRINOX for locally advanced pancreatic cancer: A systematic review and patient-level meta-analysis, Lancet Oncol., 17, 801, 10.1016/S1470-2045(16)00172-8

Hanahan, 2000, The hallmarks of cancer, Cell, 100, 57, 10.1016/S0092-8674(00)81683-9

Hanahan, 2011, Hallmarks of cancer: The next generation, Cell, 144, 646, 10.1016/j.cell.2011.02.013

Peinado, 2017, Pre-metastatic niches: Organ-specific homes for metastases, Nat. Rev. Cancer, 17, 302, 10.1038/nrc.2017.6

Aiello, 2015, Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver, Nat. Cell Biol., 17, 816, 10.1038/ncb3169

Liu, 2016, Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils, Cancer Cell, 30, 243, 10.1016/j.ccell.2016.06.021

Liu, 2016, Characteristics and Significance of the Pre-metastatic Niche, Cancer Cell, 30, 668, 10.1016/j.ccell.2016.09.011

Thery, 2002, Exosomes: Composition, biogenesis and function, Nat. Rev. Immunol., 2, 569, 10.1038/nri855

Siljander, 2015, Biological properties of extracellular vesicles and their physiological functions, J. Extracell. Vesicles, 4, 27066, 10.3402/jev.v4.27066

Luan, 2017, Engineering exosomes as refined biological nanoplatforms for drug delivery, Acta Pharmacol. Sin., 38, 754, 10.1038/aps.2017.12

S, 2013, Extracellular vesicles: Biology and emerging therapeutic opportunities, Nat. Rev. Drug Discov., 12, 347, 10.1038/nrd3978

Kamerkar, 2017, Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer, Nature, 546, 498, 10.1038/nature22341

Jang, 2013, Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors, ACS Nano, 7, 7698, 10.1021/nn402232g

Saari, 2015, Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells, J. Control. Release Off. J. Control. Release Soc., 220, 727, 10.1016/j.jconrel.2015.09.031

Garofalo, 2019, Extracellular vesicles enhance the targeted delivery of immunogenic oncolytic adenovirus and paclitaxel in immunocompetent mice, J. Control. Release Off. J. Control. Release Soc., 294, 165, 10.1016/j.jconrel.2018.12.022

Hoshino, 2015, Tumour exosome integrins determine organotropic metastasis, Nature, 527, 329, 10.1038/nature15756

Gurlevik, 2016, Administration of Gemcitabine After Pancreatic Tumor Resection in Mice Induces an Antitumor Immune Response Mediated by Natural Killer Cells, Gastroenterology, 151, 338, 10.1053/j.gastro.2016.05.004

Ames, E., Canter, R.J., Grossenbacher, S.K., Mac, S., Chen, M., Smith, R.C., Hagino, T., Perez-Cunningham, J., Sckisel, G.D., and Urayama, S. (2015). NK Cells Preferentially Target Tumor Cells with a Cancer Stem Cell Phenotype. J. Immunol.

Mamessier, 2011, Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity, J. Clin. Investig., 121, 3609, 10.1172/JCI45816

Platonova, 2011, Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma, Cancer Res., 71, 5412, 10.1158/0008-5472.CAN-10-4179

Sun, 2017, High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer, Oncoimmunology, 6, e1264562, 10.1080/2162402X.2016.1264562

Cong, 2018, Dysfunction of Natural Killer Cells by FBP1-Induced Inhibition of Glycolysis during Lung Cancer Progression, Cell Metab., 28, 243, 10.1016/j.cmet.2018.06.021

Jewett, 2011, Tumor induced inactivation of natural killer cell cytotoxic function; implication in growth, expansion and differentiation of cancer stem cells, J. Cancer, 2, 443, 10.7150/jca.2.443

Li, 2012, Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO, Cancer Lett., 318, 154, 10.1016/j.canlet.2011.12.020

Sheppard, 2018, The Paradoxical Role of NKG2D in Cancer Immunity, Front. Immunol., 9, 1808, 10.3389/fimmu.2018.01808

Alter, 2004, CD107a as a functional marker for the identification of natural killer cell activity, J. Immunol. Methods, 294, 15, 10.1016/j.jim.2004.08.008

Wang, 2012, Natural killer cell-produced IFN-gamma and TNF-alpha induce target cell cytolysis through up-regulation of ICAM-1, J. Leukoc. Biol., 91, 299, 10.1189/jlb.0611308

O’Brien, K.L., and Finlay, D.K. (2019). Immunometabolism and natural killer cell responses. Nat. Rev. Immunol.

Viel, 2016, TGF-beta inhibits the activation and functions of NK cells by repressing the mTOR pathway, Sci. Signal., 9, ra19, 10.1126/scisignal.aad1884

Rouce, 2016, The TGF-β/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia, Leukemia, 30, 800, 10.1038/leu.2015.327

Peinado, 2012, Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET, Nat. Med., 18, 883, 10.1038/nm.2753

Tkach, 2016, Communication by Extracellular Vesicles: Where We Are and Where We Need to Go, Cell, 164, 1226, 10.1016/j.cell.2016.01.043

Yu, 2017, Pancreatic cancer-derived exosomes promote tumor metastasis and liver pre-metastatic niche formation, Oncotarget, 8, 63461, 10.18632/oncotarget.18831

Hamidi, 2018, Every step of the way: Integrins in cancer progression and metastasis, Nat. Rev. Cancer, 18, 533, 10.1038/s41568-018-0038-z

Gasser, 2005, The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor, Nature, 436, 1186, 10.1038/nature03884

Bauer, 1999, Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA, Science, 285, 727, 10.1126/science.285.5428.727

Gardiner, 2017, What Fuels Natural Killers? Metabolism and NK Cell Responses, Front. Immunol., 8, 367, 10.3389/fimmu.2017.00367

Berchem, 2016, Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-beta and miR23a transfer, Oncoimmunology, 5, e1062968, 10.1080/2162402X.2015.1062968

Chen, 2018, Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response, Nature, 560, 382, 10.1038/s41586-018-0392-8

Xia, 2017, Negative regulation of tumor-infiltrating NK cell in clear cell renal cell carcinoma patients through the exosomal pathway, Oncotarget, 8, 37783, 10.18632/oncotarget.16354

Kim, M.P., Fleming, J.B., Wang, H., Abbruzzese, J.L., Choi, W., Kopetz, S., McConkey, D.J., Evans, D.B., and Gallick, G.E. (2011). ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma. PLoS ONE, 6.

Shiozawa, 2013, Cancer stem cells and their role in metastasis, Pharmacol. Ther., 138, 285, 10.1016/j.pharmthera.2013.01.014

Lee, 2004, Elevated TGF-β1 Secretion and Down-Modulation of NKG2D Underlies Impaired NK Cytotoxicity in Cancer Patients, J. Immunol., 172, 7335, 10.4049/jimmunol.172.12.7335

Derynck, 2003, Smad-dependent and Smad-independent pathways in TGF-β family signalling, Nature, 425, 577, 10.1038/nature02006

Halder, 2005, A specific inhibitor of TGF-beta receptor kinase, SB-431542, as a potent antitumor agent for human cancers, Neoplasia, 7, 509, 10.1593/neo.04640

Yadav, 2018, Liquid biopsy in pancreatic cancer: The beginning of a new era, Oncotarget, 9, 26900, 10.18632/oncotarget.24809

Theodoraki, 2018, Clinical Significance of PD-L1(+) Exosomes in Plasma of Head and Neck Cancer Patients, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res., 24, 896, 10.1158/1078-0432.CCR-17-2664

Gonzalez, 2017, Control of Metastasis by NK Cells, Cancer Cell, 32, 135, 10.1016/j.ccell.2017.06.009

Stanietsky, 2009, The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity, Proc. Natl. Acad. Sci. USA, 106, 17858, 10.1073/pnas.0903474106

Zhang, 2018, Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity, Nat. Immunol., 19, 723, 10.1038/s41590-018-0132-0

Borghaei, 2015, Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer, N. Engl. J. Med., 373, 1627, 10.1056/NEJMoa1507643

Brahmer, 2015, Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer, N. Engl. J. Med., 373, 123, 10.1056/NEJMoa1504627

Hamid, 2013, Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma, N. Engl. J. Med., 369, 134, 10.1056/NEJMoa1305133

Morrison, 2018, Immunotherapy and Prevention of Pancreatic Cancer, Trends Cancer, 4, 418, 10.1016/j.trecan.2018.04.001

Olson, 2018, Mouse Models for Cancer Immunotherapy Research, Cancer Discov., 8, 1358, 10.1158/2159-8290.CD-18-0044

Bruns, 1999, In vivo selection and characterization of metastatic variants from human pancreatic adenocarcinoma by using orthotopic implantation in nude mice, Neoplasia, 1, 50, 10.1038/sj.neo.7900005

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