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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 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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References

  1. 1.

    Moretta L, Bottino C, Pende D, Vitale M, Mingari MC, Moretta A (2005) Human natural killer cells: molecular mechanisms controlling NK cell activation and tumour cell lysis. Immunol Lett 100:7–13

  2. 2.

    Lanier LL (1998) NK cell receptors. Annu Rev Immunol 16:359–393

  3. 3.

    Ljunggren HG, Kärre K (1990) In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today 11:237–244

  4. 4.

    Davis DM, Chiu I, Fassett M, Cohen GB, Mandelboim O, Strominger JL (1999) The human natural killer cell immune synapse. Proc Natl Acad Sci USA 96:15062–15067

  5. 5.

    Braud VM, Allan DS, O’Callaghan CA, Söderström K, D’Andrea A, Ogg GS, Lazetic S, Young NT, Bell JI, Phillips JH, Lanier LL, McMichael AJ (1998) HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391:795–799

  6. 6.

    Colonna M, Samaridis J (1995) Cloning of immunoglobulin-superfamily members associated with HLA-C and HLA-B recognition by human natural killer cells. Science 268:405–408

  7. 7.

    Bottino C, Biassoni R, Millo R, Moretta L, Moretta A (2000) The human natural cytotoxicity receptors (NCR) that induce HLA class I-independent NK cell triggering. Hum Immunol 61:1–6

  8. 8.

    North J, Bakhsh I, Marden C, Pittman H, Addison E, Navarrete C, Anderson R, Lowdell MW (2007) Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. J Immunol 178:85–94

  9. 9.

    Ogbomo H, Michaelis M, Klassert D, Doerr HW, Cinatl J Jr (2008) Resistance to cytarabine induces the up-regulation of NKG2D ligands and enhances natural killer cell lysis of leukemic cells. Neoplasia 10:1402–1410

  10. 10.

    Thorne SH, Negrin RS, Contag CH (2006) Synergistic antitumor effects of immune cell-viral biotherapy. Science 311:1780–1784

  11. 11.

    Mandelboim O, Lieberman N, Lev M, Paul L, Arnon TI, Bushkin Y, Davis DM, Strominger JL, Yewdell JW, Porgador A (2001) Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409:1055–1060

  12. 12.

    Hinshaw VS, Olsen CW, Dybdahl-Sissoko N, Evans D (1994) Apoptosis: a mechanism of cell killing by influenza A and B viruses. J Virol 68:3667–3673

  13. 13.

    Ludwig S, Planz O, Pleschka S, Wolff T (2003) Influenza-virus-induced signaling cascades: targets for antiviral therapy? Trends Mol Med 9:46–52

  14. 14.

    García-Sastre A, Egorov A, Matassov D, Brandt S, Levy DE, Durbin JE, Palese P, Muster T (1998) Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252:324–330

  15. 15.

    Bergmann M, Romirer I, Sachet M, Fleischhacker R, García-Sastre A, Palese P, Wolff K, Pehamberger H, Jakesz R, Muster T (2001) A genetically engineered influenza A virus with ras-dependent oncolytic properties. Cancer Res 61:8188–8193

  16. 16.

    Muster T, Rajtarova J, Sachet M, Unger H, Fleischhacker R, Romirer I, Grassauer A, Url A, García-Sastre A, Wolff K, Pehamberger H, Bergmann M (2004) Interferon resistance promotes oncolysis by influenza virus NS1-deletion mutants. Int J Cancer 110:15–21

  17. 17.

    Bateman AR, Harrington KJ, Kottke T, Ahmed A, Melcher AA, Gough MJ, Linardakis E, Riddle D, Dietz A, Lohse CM, Strome S, Peterson T, Simari R, Vile RG (2002) Viral fusogenic membrane glycoproteins kill solid tumour cells by nonapoptotic mechanisms that promote cross presentation of tumour antigens by dendritic cells. Cancer Res 62:6566–6578

  18. 18.

    Fernandez M, Porosnicu M, Markovic D, Barber GN (2002) Genetically engineered vesicular stomatitis virus in gene therapy: application for treatment of malignant disease. J Virol 76:895–904

  19. 19.

    Fujihara A, Kurooka M, Miki T, Kaneda Y (2008) Intratumoral injection of inactivated Sendai virus particles elicits strong antitumor activity by enhancing local CXCL10 expression and systemic NK cell activation. Cancer Immunol Immunother 57:73–84

  20. 20.

    Egorov A, Brandt S, Sereinig S, Romanova J, Ferko B, Katinger D, Grassauer A, Alexandrova G, Katinger H, Muster T (1998) Transfectant influenza A viruses with long deletions in the NS1 protein grow efficiently in Vero cells. J Virol 72:6437–6441

  21. 21.

    Ogbomo H, Geiler J, Leutz A, von Kietzell K, Michaelis M, Doerr HW, Cinatl J Jr (2009) Measurement of cytotoxic T lymphocyte activity of human cytomegalovirus seropositive individuals by a highly sensitive coupled luminescent method. Med Microbiol Immunol 198:257–262

  22. 22.

    Michaelis M, Suhan T, Michaelis UR, Beek K, Rothweiler F, Tausch L, Werz O, Eikel D, Zörnig M, Nau H, Fleming I, Doerr HW, Cinatl J Jr (2006) Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells. Cell Death Differ 13:446–453

  23. 23.

    Chiossone L, Vitale C, Cottalasso F, Moretti S, Azzarone B, Moretta L, Mingari MC (2007) Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: evidence for different susceptibility of IL-2- versus IL-15-activated NK cells. Blood 109:3767–3775

  24. 24.

    Ogbomo H, Michaelis M, Kreuter J, Doerr HW, Cinatl J Jr (2007) Histone deacetylase inhibitors suppress natural killer cell cytolytic activity. FEBS Lett 581:1317–1322

  25. 25.

    Blaheta RA, Weich E, Marian D, Bereiter-Hahn J, Jones J, Jonas D, Michaelis M, Doerr HW, Cinatl J Jr (2006) Human cytomegalovirus infection alters PC3 prostate carcinoma cell adhesion to endothelial cells and extracellular matrix. Neoplasia 8:807–816

  26. 26.

    Wei S, Gamero AM, Liu JH, Daulton AA, Valkov NI, Trapani JA, Larner AC, Weber MJ, Djeu JY (1998) Control of lytic function by mitogen-activated protein kinase/extracellular regulatory kinase 2 (ERK2) in a human natural killer cell line: identification of perforin and granzyme B mobilization by functional ERK2. J Exp Med 187:1753–1765

  27. 27.

    Efferson CL, Tsuda N, Kawano K, Nistal-Villán E, Sellappan S, Yu D, Murray JL, García-Sastre A, Ioannides CG (2006) Prostate tumor cells infected with a recombinant influenza virus expressing a truncated NS1 protein activate cytolytic CD8 + cells to recognize noninfected tumour cells. J Virol 80:383–394

  28. 28.

    Owen RE, Yamada E, Thompson CI, Phillipson LJ, Thompson C, Taylor E, Zambon M, Osborn HM, Barclay WS, Borrow P (2007) Alterations in receptor binding properties of recent human influenza H3N2 viruses are associated with reduced natural killer cell lysis of infected cells. J Virol 81:11170–11178

  29. 29.

    Bryceson YT, March ME, Ljunggren HG, Long EO (2006) Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine release. Blood 107:159–166

  30. 30.

    Trinchieri G (1989) Biology of natural killer cells. Adv Immunol 47:187–376

  31. 31.

    Alsheikhly A, Orvell C, Härfast B, Andersson T, Perlmann P, Norrby E (1983) Sendai-virus-induced cell-mediated cytotoxicity in vitro. The role of viral glycoproteins in cell-mediated cytotoxicity. Scand J Immunol 17:129–138

  32. 32.

    Alsheikhly AR, Orvell C, Andersson T, Perlmann P (1985) The role of serologically defined epitopes on mumps virus HN-glycoprotein in the induction of virus-dependent cell-mediated cytotoxicity. Analysis with monoclonal antibodies. Scand J Immunol 22:529–538

  33. 33.

    Wacheck V, Egorov A, Groiss F, Pfeiffer A, Fuereder T, Hoeflmayer D, Kundi M, Popow-Kraupp T, Redlberger-Fritz M, A Mueller CA, Cinatl J, Michaelis M, Geiler J, Bergmann M, Romanova J, Roethl E, Morokutti A, Wolschek M, Ferko B, Seipelt J for the FluVacc EU consortium, Dick-Gudenus R, Muster T (2009) A novel type of flu vaccine: safety and immunogenicity of replication-deficient influenza virus created by deletion of the interferon antagonist NS1. J Infect Dis (in press)

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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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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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Keywords

  • Cytotoxicity
  • NK cell priming
  • Major histocompatibility complex class I
  • Degranulation
  • Oncolytic influenza A virus