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

Beteiligte Einrichtungen

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.

Bibliografische Daten

OriginalspracheEnglisch
ISSN2041-1723
DOIs
StatusVeröffentlicht - 15.05.2024

Anmerkungen des Dekanats

© 2024. The Author(s).

PubMed 38750019