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Activation of a glioma-specific immune response by oncolytic parvovirus Minute Virus of Mice infection

Cancer Gene Therapy volume 19, pages 468–475 (2012)Cite this article

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Abstract

Rodent autonomous parvoviruses (PVs) are endowed with oncotropic properties and represent virotherapeutics with inherent oncolytic features. This work aimed to evaluate the capacity of Minute Virus of Mice (MVMp) to act as an adjuvant stimulating a mouse glioblastoma-specific immune response. MVMp was shown to induce cell death through apoptosis in glioma GL261 cells. Antigen-presenting cells (APCs) provide the initial cue for innate and adaptive immune responses, and thus MVMp-infected GL261 cells were tested for their ability to activate dendritic cells (DCs) and microglia (MG), two distinct cell types that are able to act as APCs. MG and discrete DC subsets were activated after co-culture with MVMp-infected glioma GL261 cells, as evidenced by upregulation of specific activation markers (CD80, CD86) and release of proinflammatory cytokines (tumor necrosis factor-α and interleukin-6). The in vivo analysis of immunodeficient and immunocompetent mice revealed a clear difference in their susceptibility to MVMp-mediated tumor suppression. Immunocompetent mice were fully protected from tumor outgrowth of GL261 cells infected ex vivo with MVMp. In contrast, immunodeficient animals were less competent for MVMp-dependent tumor inhibition, with only 20% of the recipients being protected, arguing for an additional immune component to allow full tumor suppression. In keeping with this conclusion, immunocompetent mice engrafted with MVMp-infected glioma cells developed a level of anti-tumor immunity with isolated splenocytes producing elevated levels of interferon-γ. In rechallenge experiments using uninfected GL261 cells, we could show complete protection against the tumor, arguing for the induction of a T-cell-mediated, tumor-specific, long-term memory response. These findings indicate that the anticancer effect of PVs can be traced back not only for their direct oncolytic effect, but also to their ability to break tumor tolerance.

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References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987–996.

    Article  CAS  PubMed  Google Scholar 

  2. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ . Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 2006; 7: 392–401.

    Article  CAS  PubMed  Google Scholar 

  3. Rommelaere J, Geletneky K, Angelova AL, Daeffler L, Dinsart C, Kiprianova I et al. Oncolytic parvoviruses as cancer therapeutics. Cytokine Growth Factor Rev 2010; 21: 185–195.

    Article  CAS  PubMed  Google Scholar 

  4. Rommelaere J, Cornelis JJ . Antineoplastic activity of parvoviruses. J Virol Methods 1991; 33: 233–251.

    Article  CAS  PubMed  Google Scholar 

  5. Di Piazza M, Mader C, Geletneky K, Herrero YCM, Weber E, Schlehofer J et al. Cytosolic activation of cathepsins mediates parvovirus H-1-induced killing of cisplatin and TRAIL-resistant glioma cells. J Virol 2007; 81: 4186–4198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Geletneky K, Kiprianova I, Ayache A, Koch R, Herrero YCM, Deleu L et al. Regression of advanced rat and human gliomas by local or systemic treatment with oncolytic parvovirus H-1 in rat models. Neuro Oncol 2010; 12: 804–814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Moehler MH, Zeidler M, Wilsberg V, Cornelis JJ, Woelfel T, Rommelaere J et al. Parvovirus H-1-induced tumor cell death enhances human immune response in vitro via increased phagocytosis, maturation, and cross-presentation by dendritic cells. Hum Gene Ther 2005; 16: 996–1005.

    Article  CAS  PubMed  Google Scholar 

  8. Raykov Z, Grekova S, Galabov AS, Balboni G, Koch U, Aprahamian M et al. Combined oncolytic and vaccination activities of parvovirus H-1 in a metastatic tumor model. Oncol Rep 2007; 17: 1493–1499.

    PubMed  Google Scholar 

  9. Giese NA, Raykov Z, DeMartino L, Vecchi A, Sozzani S, Dinsart C et al. Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice. Cancer Gene Ther 2002; 9: 432–442.

    Article  CAS  PubMed  Google Scholar 

  10. Szatmari T, Lumniczky K, Desaknai S, Trajcevski S, Hidvegi EJ, Hamada H et al. Detailed characterization of the mouse glioma 261 tumor model for experimental glioblastoma therapy. Cancer Sci 2006; 97: 546–553.

    Article  CAS  PubMed  Google Scholar 

  11. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993; 90: 3539–3543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mach N, Gillessen S, Wilson SB, Sheehan C, Mihm M, Dranoff G . Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony-stimulating factor or Flt3-ligand. Cancer Res 2000; 60: 3239–3246.

    CAS  PubMed  Google Scholar 

  13. Burudi EM, Riese S, Stahl PD, Regnier-Vigouroux A . Identification and functional characterization of the mannose receptor in astrocytes. Glia 1999; 25: 44–55.

    Article  CAS  PubMed  Google Scholar 

  14. Zolotukhin S, Byrne BJ, Mason E, Zolotukhin I, Potter M, Chesnut K et al. Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield. Gene Therapy 1999; 6: 973–985.

    Article  CAS  PubMed  Google Scholar 

  15. Feinberg AP, Vogelstein B . A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 1983; 132: 6–13.

    Article  CAS  PubMed  Google Scholar 

  16. Cole GA . Interferon-gamma ELISPOT assay for the quantitative measurement of antigen-specific murine CD8+ T-cells. Methods Mol Biol 2005; 302: 191–204.

    CAS  PubMed  Google Scholar 

  17. Ran Z, Rayet B, Rommelaere J, Faisst S . Parvovirus H-1-induced cell death: influence of intracellular NAD consumption on the regulation of necrosis and apoptosis. Virus Res 1999; 65: 161–174.

    Article  CAS  PubMed  Google Scholar 

  18. Abschuetz A, Kehl T, Geibig R, Leuchs B, Rommelaere J, Regnier-Vigouroux A . Oncolytic murine autonomous parvovirus, a candidate vector for glioma gene therapy, is innocuous to normal and immunocompetent mouse glial cells. Cell Tissue Res 2006; 325: 423–436.

    Article  CAS  PubMed  Google Scholar 

  19. Tesniere A, Apetoh L, Ghiringhelli F, Joza N, Panaretakis T, Kepp O et al. Immunogenic cancer cell death: a key-lock paradigm. Curr Opin Immunol 2008; 20: 504–511.

    Article  CAS  PubMed  Google Scholar 

  20. Steinman RM, Banchereau J . Taking dendritic cells into medicine. Nature 2007; 449: 419–426.

    Article  CAS  PubMed  Google Scholar 

  21. Nestle FO, Banchereau J, Hart D . Dendritic cells: on the move from bench to bedside. Nat Med 2001; 7: 761–765.

    Article  CAS  PubMed  Google Scholar 

  22. Mellman I, Steinman RM . Dendritic cells: specialized and regulated antigen processing machines. Cell 2001; 106: 255–258.

    Article  CAS  PubMed  Google Scholar 

  23. Kaur G, Han SJ, Yang I, Crane C . Microglia and central nervous system immunity. Neurosurg Clin N Am 2010; 21: 43–51.

    Article  PubMed  Google Scholar 

  24. Lumniczky K, Desaknai S, Mangel L, Szende B, Hamada H, Hidvegi EJ et al. Local tumor irradiation augments the antitumor effect of cytokine-producing autologous cancer cell vaccines in a murine glioma model. Cancer Gene Ther 2002; 9: 44–52.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to B Leuchs and to Dr N Salome for providing virus stock and the 3D9 monoclonal antibody, respectively. SG was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe, Grant No. 10-2183-Mö-1 (Koch/Möhler)).

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Authors and Affiliations

  1. Department F010 and Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 701, German Cancer Research Center (DKFZ), Infection and Cancer Program, Heidelberg, Germany

    S P Grekova, Z Raykov & J Rommelaere

  2. Division F030, Department of Viral Transformation Mechanisms, German Cancer Research Center, Heidelberg, Germany

    R Zawatzky

  3. Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute for Experimental Cancer Research (ISREC), Lausanne, Switzerland

    U Koch

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  1. S P Grekova
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Correspondence to U Koch.

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Grekova, S., Raykov, Z., Zawatzky, R. et al. Activation of a glioma-specific immune response by oncolytic parvovirus Minute Virus of Mice infection. Cancer Gene Ther 19, 468–475 (2012). https://doi.org/10.1038/cgt.2012.20

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