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 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 Carlo, Michela Muscolini, Maureen Higgins, Mirte 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 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 Montfoort, Jean-Simon Diallo, Henner F. Farin, Tommy Alain and David Olagnier ()
Additional contact information
Naziia Kurmasheva: Aarhus University
Aida Said: University of Ottawa
Boaz Wong: University of Ottawa
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
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
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
Rozanne Arulanandam: Ottawa Hospital Research Insitute
Angelina Bardoul: CHUM Research Centre
Tong Tong: Aarhus University Hospital
Attila Ozsvar: 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
Laureano Vega: University of Dundee
Walid A. M. Elgaher: Saarland University
Anders R. Korshoej: Aarhus 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
Markus M. Rinschen: Aarhus University
Nadine Montfoort: Leiden University Medical Center
Jean-Simon Diallo: University of Ottawa
Henner F. Farin: Institute for Tumor Biology and Experimental Therapy
Tommy Alain: University of Ottawa
David Olagnier: Aarhus University

Nature Communications, 2024, vol. 15, issue 1, 1-28

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48422-x

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