Syncytial death mediated by oncolytic rVSV-NDV dynamically activates immunogenic apoptosis and necroptosis in human lung cancer cells
Year: 2025
Type: article
Abstract: Recent work has indicated that oncolytic virotherapy leads to immunogenic cell death (ICD) as an important mechanism of action; however, the underlying cell death pathways leading to ICD have been less explored. Our previous data demonstrated that chimeric oncolytic recombinant vesicular stomatitis virus-Newcastle disease virus (rVSV-NDV) has a strong immune-stimulating potential that seems to be mediated by immunogenic syncytial oncolysis. In this work, we aimed to investigate the role of apoptosis and necroptosis in mediating syncytial cell death. In human lung cancer cell lines (A549 and H1437), we demonstrate that fusogenic rVSV-NDV and the parental virus, rVSV, both dynamically engage apoptosis and necroptosis signaling to mediate oncolysis. Genetic deletion of key death regulators (caspase-3, caspase-8, RIPK1, RIPK3, and MLKL) by CRISPR-Cas9 further illustrated a cell line-dependent flexibility to switch to alternative, non-apoptotic or non-necroptotic pathways, while maintaining viral replication and net oncolysis. Interestingly, genetic deletion of caspase-3 prolonged the syncytial phenotype and delayed their collapse, suggesting a crucial role of caspases during syncytial death. In vitro coculture experiments further revealed that rVSV-NDV-derived oncolysates induced significantly higher levels of differentiation and activation of human monocyte-derived dendritic cells than non-fusogenic rVSV-infected oncolysates. This illustrates the superior immunogenic potential inherent in fusogenic oncolytic viruses and warrants their further preclinical evaluation as next-generation, immune-modulating oncolytic virotherapies.
Source: Molecular Therapy Oncology
Authors: Fabian Kortum, Nina Hartmann, Alexander Bryan, Sonja Glauß, Jennifer Altomonte
Institutions: TUM Klinikum, Technical University of Munich
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,900
Awards: A multifaceted cancer immunotherapy based on an immune checkpoint-modulating chimeric oncolytic virus vector in combination with a dendritic cell vaccine, Entwicklung einer optimierten onkolytischen Virus Therapie zur Modulation der extrazellulären Matrix bei Adenokarzinom der Bauchspeicheldrüse, G8629707781
OpenAlex ID: W4412979729