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

• Published in: Nature communications Vol. 8; no. 1; p. 15327
• Main Authors: Kallert, Sandra M., Darbre, Stephanie, Bonilla, Weldy V., Kreutzfeldt, Mario, Page, Nicolas, Müller, Philipp, Kreuzaler, Matthias, Lu, Min, Favre, Stéphanie, Kreppel, Florian, Löhning, Max, Luther, Sanjiv A., Zippelius, Alfred, Merkler, Doron, Pinschewer, Daniel D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.05.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/21; 13/31; 13/44; 13/51; 38/109; 38/22; 38/23; 38/39; 38/77; 45/88; 45/90; 631/250/2152/1566/1618; 631/250/590/1867; 631/326/596/2561; 64/110; 64/60; 692/4028/67/1059/4042; 82/29; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15327

Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTL eff ) responses. Conversely, the induction of protective tumour-specific CTL eff 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 CTL eff 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 CTL eff 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. Viruses trigger potent cytotoxic T cell responses, whereas anti-tumour immunity has been difficult to establish. Here the authors engineer a replicating viral delivery system for tumour-associated antigens, which induces alarmin release, innate activation and protective anti-tumour immunity in mice.