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Replicating viral vector platform exploits alarmin signals for potent CD8+ T cell-mediated tumour immunotherapy

Author

Listed:
  • Sandra M. Kallert

    (University of Basel)

  • Stephanie Darbre

    (Departement de Pathologie et Immunologie, Centre Médical Universitaire, University of Geneva)

  • Weldy V. Bonilla

    (University of Basel)

  • Mario Kreutzfeldt

    (Departement de Pathologie et Immunologie, Centre Médical Universitaire, University of Geneva
    Geneva University Hospital, Centre Médical Universitaire)

  • Nicolas Page

    (Departement de Pathologie et Immunologie, Centre Médical Universitaire, University of Geneva)

  • Philipp Müller

    (University Hospital and University of Basel
    Present address: Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400 Biberach an der Riss, Germany)

  • Matthias Kreuzaler

    (University Hospital and University of Basel)

  • Min Lu

    (University of Basel)

  • Stéphanie Favre

    (Center for Immunity and Infection Lausanne, University of Lausanne)

  • Florian Kreppel

    (Witten/Herdecke University (UW/H), Faculty of Health/School of Medicine)

  • Max Löhning

    (Experimental Immunology and Osteoarthritis Research, Charité–Universitätsmedizin Berlin
    Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), Leibniz Institute)

  • Sanjiv A. Luther

    (Center for Immunity and Infection Lausanne, University of Lausanne)

  • Alfred Zippelius

    (University Hospital and University of Basel
    University Hospital Basel)

  • Doron Merkler

    (Departement de Pathologie et Immunologie, Centre Médical Universitaire, University of Geneva
    Geneva University Hospital, Centre Médical Universitaire)

  • Daniel D. Pinschewer

    (University of Basel)

Abstract

Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTLeff) responses. Conversely, the induction of protective tumour-specific CTLeff and their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTLeff responses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTLeff influx triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy.

Suggested Citation

  • Sandra M. Kallert & Stephanie Darbre & Weldy V. Bonilla & Mario Kreutzfeldt & Nicolas Page & Philipp Müller & Matthias Kreuzaler & Min Lu & Stéphanie Favre & Florian Kreppel & Max Löhning & Sanjiv A. , 2017. "Replicating viral vector platform exploits alarmin signals for potent CD8+ T cell-mediated tumour immunotherapy," Nature Communications, Nature, vol. 8(1), pages 1-13, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15327
    DOI: 10.1038/ncomms15327
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