Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways
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Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways. / Kurmasheva, Naziia; Said, Aida; Wong, Boaz; Kinderman, Priscilla; Han, Xiaoying; Rahimic, Anna H F; Kress, Alena; Carter-Timofte, Madalina E; Holm, Emilia; van der Horst, Demi; Kollmann, Christoph F; Liu, Zhenlong; Wang, Chen; Hoang, Huy-Dung; Kovalenko, Elina; Chrysopoulou, Maria; Twayana, Krishna Sundar; Ottosen, Rasmus N; Svenningsen, Esben B; Begnini, Fabio; Kiib, Anders E; Kromm, Florian E H; Weiss, Hauke J; Di Carlo, Daniele; Muscolini, Michela; Higgins, Maureen; van der Heijden, Mirte; Bardoul, Angelina; Tong, Tong; Ozsvar, Attila; Hou, Wen-Hsien; Schack, Vivien R; Holm, Christian K; Zheng, Yunan; Ruzek, Melanie; Kalucka, Joanna; de la Vega, Laureano; Elgaher, Walid A M; Korshoej, Anders R; Lin, Rongtuan; Hiscott, John; Poulsen, Thomas B; O'Neill, Luke A; Roy, Dominic G; Rinschen, Markus M; van Montfoort, Nadine; Diallo, Jean-Simon; Farin, Henner F; Alain, Tommy; Olagnier, David.
in: NAT COMMUN, Jahrgang 15, Nr. 1, 15.05.2024, S. 4096.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 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
N1 - © 2024. The Author(s).
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
U2 - 10.1038/s41467-024-48422-x
DO - 10.1038/s41467-024-48422-x
M3 - SCORING: Journal article
C2 - 38750019
VL - 15
SP - 4096
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -