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.
Highlights
Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTLeff) responses
The arenavirus promoter consists of an intra-segmental RNA hybrid formed by a highly conserved stretch of 19–21 terminal nucleotides in each segment’s 50UTR and 30UTR
Inflammatory activation of the tumour microenvironment in artLCMV-OVA immunotherapy whereas the accompanying non-specific inflammation, which was induced by artLCMV-GFP, was insufficient to mediate these effects in full. These results identify virally delivered alarmin signals as key drivers of protective CTLeff responses in vectored cancer immunotherapy
Summary
Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTLeff) responses. Lymphocytic choriomeningitis virus (LCMV), the prototype member of the arenavirus family, elicits CTLeff responses of high magnitude and cytolytic capacity, in combination with life-long CTL immunity. These features, together with a low hazard profile for humans, have rendered it a primary workhorse of immunologists since the 1930s Studies in accidentally LCMV-infected laboratory workers have confirmed that, analogously to mice, high frequencies of effector memory CTL are maintained for several years after a single acute infection[20] These features in combination with low seroprevalence in the human population[21,22] raised our interest in LCMV as a live-attenuated cancer immunotherapy platform, to deliver TAA-specific immunization alongside with potent innate immune activation
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