title: Differential expression of ligands for NKG2D and DNAM-1 receptors by epithelial ovarian cancer-derived exosomes and its influence on NK cell cytotoxicity.
abstract: 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.
authors.affiliation: Department of Clinical Microbiology/Clinical Immunology, Umeå University, S-90185, Umeå, Sweden.
authors.forename: Alireza
authors.initials: A
authors.lastname: Labani-Motlagh
authors.affiliation: Department of Clinical Microbiology/Clinical Immunology, Umeå University, S-90185, Umeå, Sweden.|Department of Clinical Sciences/Obstetrics and Gynaecology, Umeå University, S-90185, Umeå, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Israelsson
authors.affiliation: Department of Clinical Sciences/Obstetrics and Gynaecology, Umeå University, S-90185, Umeå, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Ottander
authors.affiliation: Department of Biomedical Sciences/Pathology, Umeå University, S-90185, Umeå, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Lundin
authors.affiliation: Department of Clinical Microbiology/Clinical Immunology, Umeå University, S-90185, Umeå, Sweden.
authors.forename: Ivan
authors.initials: I
authors.lastname: Nagaev
authors.affiliation: Department of Clinical Microbiology/Clinical Immunology, Umeå University, S-90185, Umeå, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Nagaeva
authors.affiliation: Department of Clinical Microbiology/Clinical Immunology, Umeå University, S-90185, Umeå, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Dehlin
authors.affiliation: Department of Clinical Microbiology/Clinical Immunology, Umeå University, S-90185, Umeå, Sweden.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Baranov
authors.affiliation: Department of Clinical Microbiology/Clinical Immunology, Umeå University, S-90185, Umeå, Sweden. lucia.mincheva-nilsson@umu.se.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mincheva-Nilsson
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D055354:Exosomes / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K
keywords: Cytotoxicity; DNAM-1/CD266; Epithelial ovarian cancer/EOC; Exosomes; MICA/B; NKG2D; Nectin-2; PVR; Tumor; ULBP