Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/4107583

Documents

In Collections

This item can be found in the following collections:

Kurmasheva, N.; Said, A.; Wong, B.Z.; Kinderman, P.; Han, X.Y.; Rahimic, A.H.F.; ... ; Olagnier, D. (2024)

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

Article / Letter to editor
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...Show moreThe 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.
Show less
All authors
Kurmasheva, N.; Said, A.; Wong, B.Z.; Kinderman, P.; Han, X.Y.; Rahimic, A.H.F.; Kress, A.; Carter-Timofte, M.E.; Holm, E.; Horst, D. van der; Kollmann, C.F.; Liu, Z.L.; Wang, C.; Hoang, H.D.; Kovalenko, E.; Chrysopoulou, M.; Twayana, K.S.; Ottosen, R.N.; Svenningsen, E.B.; Begnini, F.; Kiib, A.E.; Kromm, F.E.H.; Weiss, H.J.; Carlo, D. di; Muscolini, M.; Higgins, M.; Heijden, M. van der; Bardoul, A.; Tong, T.; Ozsvar, A.; Hou, W.H.; Schack, V.R.; Holm, C.K.; Zheng, Y.N.; Ruzek, M.; Kalucka, J.; Vega, L. de la; Elgaher, W.A.M.; Korshoej, A.R.; Lin, R.T.; Hiscott, J.; Poulsen, T.B.; O'Neill, L.A.; Roy, D.G.; Rinschen, M.M.; Montfoort, N. van; Diallo, J.S.; Farin, H.F.; Alain, T.; Olagnier, D.
Date
2024-05-15
Journal
Nature Communications
Volume
15
Issue
1
DOI
doi:10.1038/s41467-024-48422-x