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Nat Commun. 2017 May 26;8:15327. doi: 10.1038/ncomms15327.

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

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Division of Experimental Virology, Department of Biomedicine, University of Basel, Petersplatz 10, 4009 Basel, Switzerland.
Departement de Pathologie et Immunologie, Centre Médical Universitaire, University of Geneva, 1 rue Michel Servet, 1211 Geneva, Switzerland.
Division of Clinical Pathology, Geneva University Hospital, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva, Switzerland.
Department of Biomedicine, University Hospital and University of Basel, Hebelstr. 20, 4031 Basel, Switzerland.
Department of Biochemistry, Center for Immunity and Infection Lausanne, University of Lausanne, Chemin des Boveresses 144, 1066 Epalinges, Switzerland.
Witten/Herdecke University (UW/H), Faculty of Health/School of Medicine, Stockumer Str. 10, 58453 Witten, Germany.
Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
Department of Medical Oncology, University Hospital Basel, Hebelstr. 20, 4031 Basel, Switzerland.


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.

[Indexed for MEDLINE]
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