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Tumor cells infected with oncolytic influenza A virus prime natural killer cells for lysis of resistant tumor cells

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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 ΔNS1 IAV showed enhanced lysis when compared with mock-infected cells (93% ± 1.47 vs. 52% ± 0.74), both mock-infected and ΔNS1 IAV-infected DU145 cells were resistant to NK cell lysis. Moreover, NK cells primed with ΔNS1 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 ΔNS1 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 ΔNS1 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, ΔNS1 IAV may influence anti-tumoral responses by priming NK cells.

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Acknowledgment

The authors gratefully acknowledge the support by the organization “Hilfe für krebskranke Kinder, Frankfurt/Main e.V.”, by the foundation “Frankfurter Stiftung für krebskranke Kinder der Hilfe für krebskranke Kinder Frankfurt e.V.”, and by the European Commission-funded Co-operative Research and Specific Targeted Research Projects; COOP-CT-2004, Contract Nr. 512864 and LSHB-CT-2004, Contract Nr. 512054, respectively.

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Authors and Affiliations

  1. Institut für Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

    Henry Ogbomo, Martin Michaelis, Janina Geiler, Marijke van Rikxoort, Hans Wilhelm Doerr & Jindrich Cinatl Jr.

  2. Avir Green Hills Biotechnology AG, Vienna, Austria

    Thomas Muster & Andrej Egorov

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  1. Henry Ogbomo
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  2. Martin Michaelis
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  3. Janina Geiler
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  4. Marijke van Rikxoort
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  5. Thomas Muster
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  6. Andrej Egorov
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  7. Hans Wilhelm Doerr
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  8. Jindrich Cinatl Jr.
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Correspondence to Jindrich Cinatl Jr..

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Ogbomo, H., Michaelis, M., Geiler, J. et al. Tumor cells infected with oncolytic influenza A virus prime natural killer cells for lysis of resistant tumor cells. Med Microbiol Immunol 199, 93–101 (2010). https://doi.org/10.1007/s00430-009-0139-0

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  • DOI: https://doi.org/10.1007/s00430-009-0139-0

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