Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

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 BegniniAnders E. Kiib, Florian E.H. Kromm, Hauke J. Weiss, Daniele Di Carlo, Michela Muscolini, Maureen Higgins, Mirte van der Heijden, 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 (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    1 Citation (Scopus)
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    Abstract

    The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. 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.

    Original languageEnglish
    Article number4096
    Number of pages28
    JournalNature Communications
    Volume15
    Issue number1
    DOIs
    Publication statusPublished - 15 May 2024

    Keywords

    • Animals
    • Humans
    • Oncolytic Virotherapy/methods
    • Succinates/pharmacology
    • Mice
    • Cell Line, Tumor
    • Oncolytic Viruses
    • Interferon Type I/metabolism
    • NF-E2-Related Factor 2/metabolism
    • Colonic Neoplasms/therapy
    • Antiviral Agents/pharmacology
    • NF-kappa B/metabolism
    • I-kappa B Kinase/metabolism
    • Kelch-Like ECH-Associated Protein 1/metabolism
    • Inflammation/drug therapy
    • Female
    • Vesicular stomatitis Indiana virus/physiology
    • Signal Transduction/drug effects

    ASJC Scopus subject areas

    • General Chemistry
    • General Biochemistry,Genetics and Molecular Biology
    • General Physics and Astronomy

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