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Adenovirus-mediated gene transfer of pathogen-associated molecular patterns for cancer immunotherapy

Cancer Gene Therapy volume 16, pages 310–319 (2009)Cite this article

Abstract

The delivery of stimulatory signals to dendritic cells (DCs) in the tumor microenvironment could be an effective means to break tumor-induced tolerance. The work presented here evaluates the immunostimulatory properties of pathogen-associated molecular patterns (PAMPs), microbial molecules which bind Toll-like receptors and deliver activating signals to immune cells, when expressed in tumor cells using adenoviral (Ad) vectors. In vitro, transduction of A549 tumor cells with Ad vectors expressing either flagellin from Listeria monocytogenes or P40 protein from Klebsiella pneumoniae induced the maturation of human monocyte-derived DCs in co-cultures. In mixed lymphocyte reactions (MLRs), Ad-flagellin and Ad-P40 transduction of tumor cells stimulated lymphocyte proliferation and the secretion of IFN-γ. In vivo, these vectors were used either as stand-alone immunoadjuvants injected intratumorally or as vaccine adjuvants combined with a tumor antigen-expressing vector. When Ad-PAMPs were administered intratumorally to mice bearing subcutaneous syngeneic B16F0-CAR (cocksackie-adenovirus receptor) melanomas, tumor progression was transiently inhibited by Ad-P40. In a therapeutic vaccine setting, the combination of Ad-MUC1 and Ad-PAMP vectors injected subcutaneously delayed the growth of implanted RenCa-MUC1 tumors and improved tumor rejection when compared with vaccination with Ad-MUC1 alone. These results suggest that Ad-PAMPs could be effective immunoadjuvants for cancer immunotherapy.

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Acknowledgements

We thank Professor Frank Brombacher for the gift of L. monocytogenes DNA, Professor Volker Schirrmacher for the gift of NDV-HN monoclonal antibody, Dr Ronald Rooke and Dr Joerg Schneider for critical review of this paper.

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Author notes

  1. P Von Hoegen

    Present address: 4Current address: The Weinberg Group LLC, Brussels, Belgium.,

Authors and Affiliations

  1. Molecular Immunology Department, Transgene, Strasbourg, France

    C Tosch, M Geist, C Ledoux, C Ziller-Remi, S Paul, P Erbs, J-M Balloul & H Haegel

  2. Centre d'Immunologie Pierre Fabre, Saint Julien en Genevoix, France

    N Corvaia

  3. Euraccine, Lasne, Belgium

    P Von Hoegen

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  1. C Tosch
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  2. M Geist
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Correspondence to H Haegel.

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Tosch, C., Geist, M., Ledoux, C. et al. Adenovirus-mediated gene transfer of pathogen-associated molecular patterns for cancer immunotherapy. Cancer Gene Ther 16, 310–319 (2009). https://doi.org/10.1038/cgt.2008.85

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