title: Antibody-dependent cell lysis by NK cells is preserved after sarcoma-induced inhibition of NK cell cytotoxicity.
abstract: Osteosarcoma and Ewing's sarcoma tumor cells are susceptible to IL15-induced or antibody-mediated cytolytic activity of NK cells in short-term cytotoxicity assays. When encountering the tumor environment in vivo, NK cells may be in contact with tumor cells for a prolonged time period. We explored whether a prolonged interaction with sarcoma cells can modulate the activation and cytotoxic activity of NK cells. The 40 h coculture of NK cells with sarcoma cells reversibly interfered with the IL15-induced expression of NKG2D, DNAM-1 and NKp30 and inhibited the cytolytic activity of NK cells. The inhibitory effects on receptor expression required physical contact between NK cells and sarcoma cells and were independent of TGF-β. Five days pre-incubation of NK cells with IL15 prevented the down-regulation of NKG2D and cytolytic activity in subsequent cocultures with sarcoma cells. NK cell FcγRIIIa/CD16 receptor expression and antibody-mediated cytotoxicity were not affected after the coculture. Inhibition of NK cell cytotoxicity was directly linked to the down-regulation of the respective NK cell-activating receptors. Our data demonstrate that the inhibitory effects of sarcoma cells on the cytolytic activity of NK cells do not affect the antibody-dependent cytotoxicity and can be prevented by pre-activation of NK cells with IL15. Thus, the combination of cytokine-activated NK cells and monoclonal antibody therapy may be required to improve tumor targeting and NK cell functionality in the tumor environment.
authors.affiliation: Department of Pediatrics, Leiden University Medical Centre, Leiden, The Netherlands. j.h.w.pahl@lumc.nl
authors.forename: Jens H W
authors.initials: JH
authors.lastname: Pahl
authors.forename: S Eriaty N
authors.initials: SE
authors.lastname: Ruslan
authors.forename: Kitty M C
authors.initials: KM
authors.lastname: Kwappenberg
authors.forename: Monique M
authors.initials: MM
authors.lastname: van Ostaijen-Ten Dam
authors.forename: Maarten J D
authors.initials: MJ
authors.lastname: van Tol
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Lankester
authors.forename: Marco W
authors.initials: MW
authors.lastname: Schilham
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000096:biosynthesis; D012516:Osteosarcoma / Q000276:immunology*; D017452:Receptors, IgG / Q000096:biosynthesis; D055607:Receptors, Natural Killer Cell; D012512:Sarcoma, Ewing / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D019409:Interleukin-15; C527085:KLRK1 protein, human; C431710:NCR3 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055628:Natural Cytotoxicity Triggering Receptor 3; D017452:Receptors, IgG; D055607:Receptors, Natural Killer Cell; D016212:Transforming Growth Factor beta