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Differential expression of ligands for NKG2D and DNAM-1 receptors by epithelial ovarian cancer-derived exosomes and its influence on NK cell cytotoxicity
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2016 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 4, 5455-5466 p.Article in journal (Refereed) Published
Abstract [en]

Cancers constitutively produce and secrete into the blood and other biofluids 30-150 nm-sized endosomal vehicles called exosomes. Cancer-derived exosomes exhibit powerful influence on a variety of biological mechanisms to the benefit of the tumors that produce them. We studied the immunosuppressive ability of epithelial ovarian cancer (EOC) exosomes on two cytotoxic pathways of importance for anticancer immunity-the NKG2D receptor-ligand pathway and the DNAM-1-PVR/nectin-2 pathway. Using exosomes, isolated from EOC tumor explant and EOC cell-line culture supernatants, and ascitic fluid from EOC patients, we studied the expression of NKG2D and DNAM-1 ligands on EOC exosomes and their ability to downregulate the cognate receptors. Our results show that EOC exosomes differentially and constitutively express NKG2D ligands from both MICA/B and ULBP families on their surface, while DNAM-1 ligands are more seldom expressed and not associated with the exosomal membrane surface. Consequently, the NKG2D ligand-bearing EOC exosomes significantly downregulated the NKG2D receptor expression on peripheral blood mononuclear cells (PBMC) while the DNAM-1 receptor was unaffected. The downregulation of NKG2D receptor expression was coupled to inhibition of NKG2D receptor-ligand-mediated degranulation and cytotoxicity measured in vitro with OVCAR-3 and K562 cells as targets. The EOC exosomes acted as a decoy impairing the NKG2D mediated cytotoxicity while the DNAM-1 receptor-ligand system remained unchanged. Taken together, our results support and explain the mechanism behind the recently reported finding that in EOC, NK-cell recognition and killing of tumor cells was mainly dependent on DNAM-1 signaling while the contribution of the NKG2D receptor-ligand pathway was complementary and uncertain.

Place, publisher, year, edition, pages
2016. Vol. 37, no 4, 5455-5466 p.
Keyword [en]
Epithelial ovarian cancer/EOC, Tumor, Exosomes, NKG2D, DNAM-1/CD266, Cytotoxicity, MICA/B, ULBP, PVR, Nectin-2
National Category
Cancer and Oncology Immunology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-118529DOI: 10.1007/s13277-015-4313-2ISI: 000374904500128PubMedID: 26563374OAI: oai:DiVA.org:umu-118529DiVA: diva2:913744
Available from: 2016-03-22 Created: 2016-03-22 Last updated: 2017-08-16Bibliographically approved
In thesis
1. Immune modulation in serous epithelial ovarian cancer: focus on the role of tumor-derived exosomes
Open this publication in new window or tab >>Immune modulation in serous epithelial ovarian cancer: focus on the role of tumor-derived exosomes
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Serous epithelial ovarian cancer (EOC) is a potent suppressor of the immune defense. Here, we studied interactions between EOC and the immune system that lead to escape from tumor immune surveillance. We explored: 1) tumor escape from cytotoxicity by exosome-mediated modulation of the NK-cell receptors NKG2D and DNAM-1; 2) cytokine mRNA profiles in the EOC microenvironment and peripheral blood and their role in the suppression of the anti-tumor immune responses; 3) expression of long non-coding (lnc) RNAs in EOC tumors and exosomes.

We found that EOC-secreted exosomes carried MICA/B and ULBP1-3, ligands of NKG2D, and could downregulate the NKG2D receptor and impair NKG2D-mediated cytotoxicity. In contrast, the DNAM-1 receptor ligands PVR and nectin-2 were seldom found in exosomes and were not associated with the exosomal membrane leaving the DNAM-1 receptor-mediated cytotoxicity intact. We compared cytokine mRNA expression in the tumor microenvironment and in immune cells of peripheral blood in EOC patients and patients with benign ovarian conditions. EOC patients were unable to mount an IFN-gamma mRNA response needed for tumor cell elimination. Instead, there was a significant up-regulation of inflammation and immune suppression i.e. responses promoting tumorigenesis and T-regulatory cell priming that suppress anti-tumor immunity. In addition, we studied lncRNAs in tissues and sera exosomes from EOC and benign ovarian conditions aiming to assess the lncRNA(s) expression profile and look for lncRNA(s) as possible marker(s) for early diagnosis. We found a deregulated lncRNAs expression in EOC tissues that correlated well with the lncRNAs expression in exosomes. Candidate lncRNAs with the highest expression and abundance were suggested for evaluation as EOC diagnostic markers in a future large cohort study.

Our studies of EOC tissue and EOC exosomes highlight the immunosuppressive tumor microenvironment and the complex tumor exosome-mediated network of immunosuppressive mechanisms, and provide a mechanistic explanation of the observation that NKG2D-mediated cytotoxicity does not function in EOC patients and is partially replaced by the accessory DNAM-1 dependent cytotoxic pathway. The deregulated lncRNAs expression in EOC tissues and exosomes might serve for diagnostic purposes but could also be a potential risk of spreading tumor-derived lncRNAs in EOC exosomes to recipient cells throughout the body.

Place, publisher, year, edition, pages
Umeå: Umea University, 2017. 68 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1901
Keyword
ovarian cancer, EOC, HGSC, exosomes, NKG2D, MICA/B, ULBP, DNAM-1, PVR, nectin-2, lncRNAs, immune suppression, anti-tumor immunity, NK-cell cytotoxicity, cytokines, Th1, Th2, T regulatory response, inflammation, tumor microenvironment
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-138264 (URN)978-91-7601-731-9 (ISBN)
Public defence
2017-09-15, Horsal D, Unod T9, Norrland's Universitetssjukhus, Umea, 09:00 (English)
Opponent
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Available from: 2017-08-25 Created: 2017-08-16 Last updated: 2017-10-11Bibliographically approved

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