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; Rozanne Arulanandam; 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

doi:10.1038/s41467-024-48422-x

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, Rozanne Arulanandam, 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 journal › Article › peer-review

19 Citations (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 language	English
Article number	4096
Number of pages	28
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-48422-x
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-024-48422-xLicence: CC BY

Final published versionFinal published version, 5.29 MBLicence: CC BY

Cite this

Kurmasheva, N., Said, A., Wong, B., Kinderman, P., Han, X., Rahimic, A. H. F., Kress, A., Carter-Timofte, M. E., Holm, E., van der Horst, D., Kollmann, C. F., Liu, Z., Wang, C., Hoang, H.-D., Kovalenko, E., Chrysopoulou, M., Twayana, K. S., Ottosen, R. N., Svenningsen, E. B., ... Olagnier, D. (2024). Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways. Nature Communications, 15(1), Article 4096. https://doi.org/10.1038/s41467-024-48422-x

@article{031c6e64cb044fa3813b15f0b4b2d550,

title = "Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways",

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.",

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",

author = "Naziia Kurmasheva and Aida Said and Boaz Wong and Priscilla Kinderman and Xiaoying Han and Rahimic, \{Anna H.F.\} and Alena Kress and Carter-Timofte, \{Madalina E.\} and Emilia Holm and \{van der Horst\}, Demi and Kollmann, \{Christoph F.\} and Zhenlong Liu and Chen Wang and Huy-Dung Hoang and Elina Kovalenko and Maria Chrysopoulou and Twayana, \{Krishna Sundar\} and Ottosen, \{Rasmus N\} and Svenningsen, \{Esben B.\} and Fabio Begnini and Kiib, \{Anders E.\} and Kromm, \{Florian E.H.\} and Weiss, \{Hauke J.\} and \{Di Carlo\}, Daniele and Michela Muscolini and Maureen Higgins and \{van der Heijden\}, Mirte and Rozanne Arulanandam and Angelina Bardoul and Tong Tong and Attila Ozsvar and Wen-Hsien Hou and Schack, \{Vivien R.\} and Holm, \{Christian K.\} and Yunan Zheng and Melanie Ruzek and Joanna Kalucka and \{de la Vega\}, Laureano and Elgaher, \{Walid A.M.\} and Korshoej, \{Anders R.\} and Rongtuan Lin and John Hiscott and Poulsen, \{Thomas B.\} and O'Neill, \{Luke A.\} and Roy, \{Dominic G\} and Rinschen, \{Markus M.\} and \{van Montfoort\}, Nadine and Jean-Simon Diallo and Farin, \{Henner F\} and Tommy Alain and David Olagnier",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = may,

day = "15",

doi = "10.1038/s41467-024-48422-x",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

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Kurmasheva, N, Said, A, Wong, B, Kinderman, P, Han, X, Rahimic, AHF, Kress, A, Carter-Timofte, ME, Holm, E, van der Horst, D, Kollmann, CF, Liu, Z, Wang, C, Hoang, H-D, Kovalenko, E, Chrysopoulou, M, Twayana, KS, Ottosen, RN, Svenningsen, EB, Begnini, F, Kiib, AE, Kromm, FEH, Weiss, HJ, Di Carlo, D, Muscolini, M, Higgins, M, van der Heijden, M, Arulanandam, R, Bardoul, A, Tong, T, Ozsvar, A, Hou, W-H, Schack, VR, Holm, CK, Zheng, Y, Ruzek, M, Kalucka, J, de la Vega, L, Elgaher, WAM, Korshoej, AR, Lin, R, Hiscott, J, Poulsen, TB, O'Neill, LA, Roy, DG, Rinschen, MM, van Montfoort, N, Diallo, J-S, Farin, HF, Alain, T & Olagnier, D 2024, 'Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways', Nature Communications, vol. 15, no. 1, 4096. https://doi.org/10.1038/s41467-024-48422-x

TY - JOUR

T1 - Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

AU - Kurmasheva, Naziia

AU - Said, Aida

AU - Wong, Boaz

AU - Kinderman, Priscilla

AU - Han, Xiaoying

AU - Rahimic, Anna H.F.

AU - Kress, Alena

AU - Carter-Timofte, Madalina E.

AU - Holm, Emilia

AU - van der Horst, Demi

AU - Kollmann, Christoph F.

AU - Liu, Zhenlong

AU - Wang, Chen

AU - Hoang, Huy-Dung

AU - Kovalenko, Elina

AU - Chrysopoulou, Maria

AU - Twayana, Krishna Sundar

AU - Ottosen, Rasmus N

AU - Svenningsen, Esben B.

AU - Begnini, Fabio

AU - Kiib, Anders E.

AU - Kromm, Florian E.H.

AU - Weiss, Hauke J.

AU - Di Carlo, Daniele

AU - Muscolini, Michela

AU - Higgins, Maureen

AU - van der Heijden, Mirte

AU - Arulanandam, Rozanne

AU - Bardoul, Angelina

AU - Tong, Tong

AU - Ozsvar, Attila

AU - Hou, Wen-Hsien

AU - Schack, Vivien R.

AU - Holm, Christian K.

AU - Zheng, Yunan

AU - Ruzek, Melanie

AU - Kalucka, Joanna

AU - de la Vega, Laureano

AU - Elgaher, Walid A.M.

AU - Korshoej, Anders R.

AU - Lin, Rongtuan

AU - Hiscott, John

AU - Poulsen, Thomas B.

AU - O'Neill, Luke A.

AU - Roy, Dominic G

AU - Rinschen, Markus M.

AU - van Montfoort, Nadine

AU - Diallo, Jean-Simon

AU - Farin, Henner F

AU - Alain, Tommy

AU - Olagnier, David

PY - 2024/5/15

Y1 - 2024/5/15

N2 - 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.

AB - 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.

KW - Animals

KW - Humans

KW - Oncolytic Virotherapy/methods

KW - Succinates/pharmacology

KW - Mice

KW - Cell Line, Tumor

KW - Oncolytic Viruses

KW - Interferon Type I/metabolism

KW - NF-E2-Related Factor 2/metabolism

KW - Colonic Neoplasms/therapy

KW - Antiviral Agents/pharmacology

KW - NF-kappa B/metabolism

KW - I-kappa B Kinase/metabolism

KW - Kelch-Like ECH-Associated Protein 1/metabolism

KW - Inflammation/drug therapy

KW - Female

KW - Vesicular stomatitis Indiana virus/physiology

KW - Signal Transduction/drug effects

UR - https://www.scopus.com/pages/publications/85193395304

U2 - 10.1038/s41467-024-48422-x

DO - 10.1038/s41467-024-48422-x

M3 - Article

C2 - 38750019

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4096

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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HIPK2 as a Novel Determinant of Tumour Progression and Therapeutic Resistance

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

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

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HIPK2 as a Novel Determinant of Tumour Progression and Therapeutic Resistance

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

Cite this