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 Poulsen, Luke A O'Neill, Dominic G Roy, Markus M Rinschen, Nadine van Montfoort, Jean-Simon Diallo, Henner F Farin, Tommy Alain, David Olagnier*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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
JournalNature Communications
Volume15
Issue1
Number of pages28
ISSN2041-1723
DOIs
Publication statusPublished - 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

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