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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.

Author information

1
Division of Experimental Virology, Department of Biomedicine, University of Basel, Petersplatz 10, 4009 Basel, Switzerland.
2
Departement de Pathologie et Immunologie, Centre Médical Universitaire, University of Geneva, 1 rue Michel Servet, 1211 Geneva, Switzerland.
3
Division of Clinical Pathology, Geneva University Hospital, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva, Switzerland.
4
Department of Biomedicine, University Hospital and University of Basel, Hebelstr. 20, 4031 Basel, Switzerland.
5
Department of Biochemistry, Center for Immunity and Infection Lausanne, University of Lausanne, Chemin des Boveresses 144, 1066 Epalinges, Switzerland.
6
Witten/Herdecke University (UW/H), Faculty of Health/School of Medicine, Stockumer Str. 10, 58453 Witten, Germany.
7
Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
8
Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
9
Department of Medical Oncology, University Hospital Basel, Hebelstr. 20, 4031 Basel, Switzerland.

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.

PMID:
28548102
PMCID:
PMC5458557
DOI:
10.1038/ncomms15327
[Indexed for MEDLINE]
Free PMC Article

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