title: Tumor cells infected with oncolytic influenza A virus prime natural killer cells for lysis of resistant tumor cells.
abstract: Tumor resistance to lysis by resting natural killer (NK) cells may be overcome by priming of NK cells with cytokines or by binding of NK activating receptors to ligands expressed on target cells. In this study, major histocompatibility complex class I (MHC-I)-negative LNCaP and MHC-I-positive DU145 cells were infected with genetically modified influenza A virus lacking the non-structural gene 1 (NS1 IAV). The cells were used to investigate the influence of NS1 IAV infection on NK cell lysis of tumor cells as well as to prime NK cells for lysis of LNCaP and DU145 cells. While LNCaP cells infected with DeltaNS1 IAV showed enhanced lysis when compared with mock-infected cells (93% +/- 1.47 vs. 52% +/- 0.74), both mock-infected and DeltaNS1 IAV-infected DU145 cells were resistant to NK cell lysis. Moreover, NK cells primed with DeltaNS1 IAV-infected LNCaP/DU145 cells effectively lysed resistant DU145 and sensitive LNCaP cells to a greater extent than NK cells primed with mock-infected LNCaP/DU145 or non-primed NK cells. Also, NK cell priming with DeltaNS1 IAV-infected tumor cells enhanced extracellular signal-regulated kinase phosphorylation and increased granule release in NK cells. The increased granule release was specifically mediated by NKp46, which eventually potentiated NK cells primed with DeltaNS1 IAV-infected tumor cells to overcome the inhibitory effects posed by MHC-I expression on DU145 cells. These findings show that in addition to direct lytic activity of NK cells, DeltaNS1 IAV may influence anti-tumoral responses by priming NK cells.
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Ogbomo
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.forename: Janina
authors.initials: J
authors.lastname: Geiler
authors.forename: Marijke
authors.initials: M
authors.lastname: van Rikxoort
authors.forename: Thomas
authors.initials: T
authors.lastname: Muster
authors.forename: Andrej
authors.initials: A
authors.lastname: Egorov
authors.forename: Hans Wilhelm
authors.initials: HW
authors.lastname: Doerr
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D019496:Cancer Vaccines; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D002470:Cell Survival; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000276:immunology; D050504:Oncolytic Viruses / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000821:virology
chemical_list: D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D055627:Natural Cytotoxicity Triggering Receptor 1