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

Author

Listed:
  • Naziia Kurmasheva

    (Aarhus University)

  • Aida Said

    (University of Ottawa
    Children’s Hospital of Eastern Ontario Research Institute)

  • Boaz Wong

    (University of Ottawa
    Ottawa Hospital Research Insitute)

  • Priscilla Kinderman

    (Leiden University Medical Center)

  • Xiaoying Han

    (McGill University)

  • Anna H. F. Rahimic

    (Aarhus University)

  • Alena Kress

    (Institute for Tumor Biology and Experimental Therapy
    Goethe University
    Goethe University)

  • Madalina E. Carter-Timofte

    (Aarhus University)

  • Emilia Holm

    (Aarhus University)

  • Demi Horst

    (Aarhus University)

  • Christoph F. Kollmann

    (Aarhus University)

  • Zhenlong Liu

    (McGill University)

  • Chen Wang

    (McGill University)

  • Huy-Dung Hoang

    (University of Ottawa
    Children’s Hospital of Eastern Ontario Research Institute)

  • Elina Kovalenko

    (Aarhus University)

  • Maria Chrysopoulou

    (Aarhus University)

  • Krishna Sundar Twayana

    (Aarhus University)

  • Rasmus N. Ottosen

    (Aarhus University)

  • Esben B. Svenningsen

    (Aarhus University)

  • Fabio Begnini

    (Aarhus University)

  • Anders E. Kiib

    (Aarhus University)

  • Florian E. H. Kromm

    (Aarhus University)

  • Hauke J. Weiss

    (Trinity Biomedical Sciences Institute)

  • Daniele Carlo

    (Istituto Pasteur Italia - Fondazione Cenci Bolognetti)

  • Michela Muscolini

    (Istituto Pasteur Italia - Fondazione Cenci Bolognetti)

  • Maureen Higgins

    (University of Dundee)

  • Mirte Heijden

    (Leiden University Medical Center)

  • Angelina Bardoul

    (CHUM Research Centre
    University of Montreal
    Institut du Cancer de Montréal)

  • Tong Tong

    (Aarhus University Hospital
    Aarhus University
    Copenhagen University Hospital)

  • Attila Ozsvar

    (Aarhus University
    Aarhus University)

  • Wen-Hsien Hou

    (Aarhus University)

  • Vivien R. Schack

    (Aarhus University)

  • Christian K. Holm

    (Aarhus University)

  • Yunan Zheng

    (AbbVie Inc.)

  • Melanie Ruzek

    (100 Research Drive)

  • Joanna Kalucka

    (Aarhus University
    Aarhus University Hospital)

  • Laureano Vega

    (University of Dundee)

  • Walid A. M. Elgaher

    (Saarland University)

  • Anders R. Korshoej

    (Aarhus University Hospital
    Aarhus University
    Copenhagen University Hospital)

  • Rongtuan Lin

    (McGill University)

  • John Hiscott

    (Istituto Pasteur Italia - Fondazione Cenci Bolognetti)

  • Thomas B. Poulsen

    (Aarhus University)

  • Luke A. O’Neill

    (Trinity Biomedical Sciences Institute)

  • Dominic G. Roy

    (CHUM Research Centre
    University of Montreal
    Institut du Cancer de Montréal)

  • Markus M. Rinschen

    (Aarhus University
    III. Department of Medicine and Hamburg Center for Kidney Health
    Aarhus University)

  • Nadine Montfoort

    (Leiden University Medical Center)

  • Jean-Simon Diallo

    (University of Ottawa
    Ottawa Hospital Research Insitute)

  • Henner F. Farin

    (Institute for Tumor Biology and Experimental Therapy
    Goethe University
    Frankfurt/Mainz partner site and German Cancer Research Center (DKFZ))

  • Tommy Alain

    (University of Ottawa
    Children’s Hospital of Eastern Ontario Research Institute)

  • David Olagnier

    (Aarhus University)

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.

Suggested Citation

  • Naziia Kurmasheva & Aida Said & Boaz Wong & Priscilla Kinderman & Xiaoying Han & Anna H. F. Rahimic & Alena Kress & Madalina E. Carter-Timofte & Emilia Holm & Demi Horst & Christoph F. Kollmann & Zhen, 2024. "Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways," Nature Communications, Nature, vol. 15(1), pages 1-28, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48422-x
    DOI: 10.1038/s41467-024-48422-x
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    References listed on IDEAS

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