Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways
Year: 2024
Type: article
Abstract: Altered metabolism and defective innate immune responses are hallmarks of tumor cells, creating a niche that can be exploited by viruses with oncolytic properties. However, heterogeneity in responses to oncolytic virotherapy is a barrier to clinical effectiveness. Resistance to oncolytic virotherapy exists and occurs via inhibition of viral spread within the tumor that may result in treatment failures. Here we show that the Krebs cycle-derived metabolite itaconate and its chemical derivatives or natural isomers enhance oncolytic virotherapy with VSVΔ51M in various models including resistant cancer cell lines, murine tumor biopsies, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. The strongest sensitizing effect to VSVΔ51M infection within the itaconate family is elucidated by 4-octyl itaconate (4-OI), a known activator of nuclear factor erythroid 2-related factor 2 (NRF2). Importantly, the sensitization to VSVΔ51M with 4-OI is not observed in non-cancer primary human cells, healthy mouse-derived tissues, and normal human colon organoids. Additionally, 4-OI improves the virus spread within a resistant mouse colon tumor model in vivo. Mechanistically, we found that the effect of 4-OI is not mediated by NRF2 or KEAP1. Instead, we show that 4-OI targets multiple pathways including the RIG-MAVS, the IKKβ-NF-κB and the JAK1-STAT1 pathways through the modification of cysteine residues in MAVS, IKKβ and JAK1, respectively. Here, we propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.
Source: Nature Communications
Authors: Naziia Kurmasheva, Aida Said, Boaz Wong, Priscilla Kinderman, Xiaoying Han, Anna H. F. Rahimic, Alena Kress, Madalina E. Carter-Timofte, Emilia Holm, Demi van der Horst, Christoph F. Kollmann, Zhenlong Liu, Chen Wang, Huy-Dung Hoang, Elina Kovalenko, Maria Chrysopoulou, Krishna Sundar Twayana, Rasmus N. Ottosen, Esben B. Svenningsen, Fabio Begnini, Anders E. Kiib, Florian E. H. Kromm, Hauke J. Weiss, Daniele Di Carlo, Michela Muscolini, Maureen Higgins, Mirte van der Heijden, Rozanne Arulanandam, Angelina Bardoul, Tong Tong, Attila Ozsvar, Wen-Hsien Hou, Vivien R. Schack, Christian K. Holm, Yunan Zheng, Melanie Ruzek, Joanna Kalucka, Laureano de la Vega, Walid A. M. Elgaher, Anders R. Korshoej, Rongtuan Lin, John Hiscott, Thomas B. Poulsen, Luke A. O’Neill, Dominic G. Roy, Markus M. Rinschen, Nadine van Montfoort, Jean-Simon Diallo, Henner F. Farin, Tommy Alain, David Olagnier
Institutions: Aarhus University, University of Ottawa, Children's Hospital of Eastern Ontario, Ottawa Hospital, Ottawa Hospital Research Institute, Leiden University Medical Center, Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Goethe University Frankfurt, Georg Speyer Haus, Frankfurt Cancer Institute, Trinity College Dublin, Istituto Pasteur, University of Dundee, Centre Hospitalier de l’Université de Montréal, Institut du cancer de Montréal, Université de Montréal, Aarhus University Hospital, Copenhagen University Hospital, AbbVie (United States), Steno Diabetes Center Aarhus, Helmholtz Centre for Infection Research, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, Aarhus Institute of Advanced Studies, German Cancer Research Center, Deutsches Konsortium für Translationale Krebsforschung
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: Associazione Italiana di Oncologia Medica, Dagmar Marshalls Fond, Aarhus Universitet, Aarhus Universitetshospital, Kræftens Bekæmpelse, McGill University, Hørslev-Fonden, Cancer Research Society, Børnecancerfonden, European Federation of Pharmaceutical Industries and Associations, Vissing Fonden, Arab-German Young Academy of Sciences and Humanities, Cancer Research UK, European Commission, National Research Foundation, Danmarks Grundforskningsfond, Bundesministerium für Bildung und Forschung, Aarhus Universitets Forskningsfond, Carlsbergfondet, Hessisches Ministerium für Wissenschaft und Kunst, Lundbeckfonden, Novo Nordisk, Terry Fox Research Institute, KWF Kankerbestrijding, Danmarks Frie Forskningsfond, Dansk Kræftforsknings Fond, Frimodt-Heineke Fonden, Novo Nordisk Fonden, Fabrikant Einar Willumsens Mindelegat, H. Lundbeck A/S, Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, Steno Diabetes Center Aarhus
Awards: G100265364, G1335987104, G1535250469, G1601546982, G1763645630, G2658012619, G2718054313, INnate-ImmunomeTabolIsm as Antiviral TargEt, G3367072807, G3372044100, Center for immunology of viral infections (CiViA), G3865359122, G434337789, G5241851531, G5246395086, Konsolidierung der interdisziplinären Forschungszusammenarbeit exzellenter arabischer und deutscher Nachwuchswissenschaftler*innen sowie Stärkung und Erweiterung ihrer transnationalen Netzwerke in Wissenschaft, Forschung und Innovation im Rahmen der Arab-German Young Academy of Sciences and Humanities (AGYA), G5636746606, G6448817052, G6789781151, G7158786936, G7436768760, EUbOPEN: Enabling and Unlocking biology in the OPEN, Oncolytische virussen maken de weg vrij voor effectieve immuuntherapie van kanker, G8080493566, G82452856, G8604643615, G8700326712, G8725625592, G8844910751, G983585516
OpenAlex ID: W4396929068