Nature Communications (May 2024)
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 Begnini,
- Anders 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
Affiliations
- Naziia Kurmasheva
- Department of Biomedicine, Aarhus University
- Aida Said
- Department of Biochemistry Microbiology and Immunology, University of Ottawa
- Boaz Wong
- Department of Biochemistry Microbiology and Immunology, University of Ottawa
- Priscilla Kinderman
- Department of Gastroenterology and Hepatology, Leiden University Medical Center
- Xiaoying Han
- Lady Davis Institute, Jewish General Hospital and Department of Medicine, McGill University
- Anna H. F. Rahimic
- Department of Biomedicine, Aarhus University
- Alena Kress
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy
- Madalina E. Carter-Timofte
- Department of Biomedicine, Aarhus University
- Emilia Holm
- Department of Biomedicine, Aarhus University
- Demi van der Horst
- Department of Biomedicine, Aarhus University
- Christoph F. Kollmann
- Department of Biomedicine, Aarhus University
- Zhenlong Liu
- Lady Davis Institute, Jewish General Hospital and Department of Medicine, McGill University
- Chen Wang
- Lady Davis Institute, Jewish General Hospital and Department of Medicine, McGill University
- Huy-Dung Hoang
- Department of Biochemistry Microbiology and Immunology, University of Ottawa
- Elina Kovalenko
- Department of Biomedicine, Aarhus University
- Maria Chrysopoulou
- Department of Biomedicine, Aarhus University
- Krishna Sundar Twayana
- Department of Biomedicine, Aarhus University
- Rasmus N. Ottosen
- Department of Chemistry, Aarhus University
- Esben B. Svenningsen
- Department of Chemistry, Aarhus University
- Fabio Begnini
- Department of Chemistry, Aarhus University
- Anders E. Kiib
- Department of Chemistry, Aarhus University
- Florian E. H. Kromm
- Department of Chemistry, Aarhus University
- Hauke J. Weiss
- School of Biochemistry and Immunology, Trinity College Dublin, Trinity Biomedical Sciences Institute
- Daniele Di Carlo
- Pasteur Laboratories, Istituto Pasteur Italia - Fondazione Cenci Bolognetti
- Michela Muscolini
- Pasteur Laboratories, Istituto Pasteur Italia - Fondazione Cenci Bolognetti
- Maureen Higgins
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee
- Mirte van der Heijden
- Department of Gastroenterology and Hepatology, Leiden University Medical Center
- Angelina Bardoul
- Cancer Axis, CHUM Research Centre
- Tong Tong
- Department of Neurosurgery, Aarhus University Hospital
- Attila Ozsvar
- Department of Biomedicine, Aarhus University
- Wen-Hsien Hou
- Department of Biomedicine, Aarhus University
- Vivien R. Schack
- Department of Biomedicine, Aarhus University
- Christian K. Holm
- Department of Biomedicine, Aarhus University
- Yunan Zheng
- Small Molecule Therapeutics & Platform Technologies, AbbVie Inc.
- Melanie Ruzek
- AbbVie, Bioresearch Center, 100 Research Drive
- Joanna Kalucka
- Department of Biomedicine, Aarhus University
- Laureano de la Vega
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee
- Walid A. M. Elgaher
- Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University
- Anders R. Korshoej
- Department of Neurosurgery, Aarhus University Hospital
- Rongtuan Lin
- Lady Davis Institute, Jewish General Hospital and Department of Medicine, McGill University
- John Hiscott
- Pasteur Laboratories, Istituto Pasteur Italia - Fondazione Cenci Bolognetti
- Thomas B. Poulsen
- Department of Chemistry, Aarhus University
- Luke A. O’Neill
- School of Biochemistry and Immunology, Trinity College Dublin, Trinity Biomedical Sciences Institute
- Dominic G. Roy
- Cancer Axis, CHUM Research Centre
- Markus M. Rinschen
- Department of Biomedicine, Aarhus University
- Nadine van Montfoort
- Department of Gastroenterology and Hepatology, Leiden University Medical Center
- Jean-Simon Diallo
- Department of Biochemistry Microbiology and Immunology, University of Ottawa
- Henner F. Farin
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy
- Tommy Alain
- Department of Biochemistry Microbiology and Immunology, University of Ottawa
- David Olagnier
- Department of Biomedicine, Aarhus University
- DOI
- https://doi.org/10.1038/s41467-024-48422-x
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
