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 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 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 af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

2 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	4096
Tidsskrift	Nature Communications
Vol/bind	15
Nummer	1
Antal sider	28
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-024-48422-x
Status	Udgivet - maj 2024

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

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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), Artikel 4096. https://doi.org/10.1038/s41467-024-48422-x

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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 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 Thomas Poulsen 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",

year = "2024",

month = may,

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

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

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, 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, T, 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, bind 15, nr. 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 - 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

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

Y1 - 2024/5

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 - http://www.scopus.com/inward/record.url?scp=85193395304&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-48422-x

DO - 10.1038/s41467-024-48422-x

M3 - Journal 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

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