Itaconate enhances oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

Naziia Kurmasheva; Aida Said; Boaz Wong; Alena Kress; Zhenlong Liu; Chen Wang; Madalina Elena Carter-Timofte; Emilia Holm; Demi van der Horst; Huy-Dung Hoang; Krishna Sundar Twayana; Rasmus Ottosen; Esben Bjerregaard Svenningsen; Fabio Begnini; Anders Engsted Kiib; Hauke Weiss; Daniele Di Carlo; Michela Muscolini; Maureen Higgins; Priscilla Kinderman; Mirte van der Heijden; Tong Tong; Attila Ozsvar; Wen-Hsien Hou; Vivien Schack; Christian Bach Holm; Nadine van Montfoort; Yunan Zheng; Melanie Ruzek; Joanna Maria Kalucka; Laureano de la Vega; Walid A M Elgaher; Anders Rosendal Korshoej; Rongtuan Lin; John Hiscottt; Thomas Poulsen; Luke O´Neill; Jean Simon Diallo; Henner Farin; Tommy Alain; David Pierre Christophe Olagnier

doi:10.21203/rs.3.rs-3035315/v1

Itaconate enhances oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

Naziia Kurmasheva, Aida Said, Boaz Wong, Alena Kress, Zhenlong Liu, Chen Wang, Madalina Elena Carter-Timofte, Emilia Holm, Demi van der Horst, Huy-Dung Hoang, Krishna Sundar Twayana, Rasmus Ottosen, Esben Bjerregaard Svenningsen, Fabio Begnini, Anders Engsted Kiib, Hauke Weiss, Daniele Di Carlo, Michela Muscolini, Maureen Higgins, Priscilla KindermanMirte van der Heijden, Tong Tong, Attila Ozsvar, Wen-Hsien Hou, Vivien Schack, Christian Bach Holm, Nadine van Montfoort, Yunan Zheng, Melanie Ruzek, Joanna Maria Kalucka, Laureano de la Vega, Walid A M Elgaher, Anders Rosendal Korshoej, Rongtuan Lin, John Hiscottt, Thomas Poulsen, Luke O´Neill, Jean Simon Diallo, Henner Farin, Tommy Alain, David Pierre Christophe Olagnier

Research output: Working paper/Preprint › Preprint

Abstract

Altered metabolism and defective innate immune responses are hallmarks of tumor cells, creating a niche that can be exploited by viruses with oncolytic properties. However, heterogeneity in responses to oncolytic virotherapy is a barrier to clinical effectiveness. Resistance to oncolytic virotherapy exists and occurs via inhibition of viral spread within the tumor that may result in treatment failures. Here we show that the Krebs cycle-derived metabolite itaconate and its chemical derivatives or natural isomers enhance oncolytic virotherapy with VSVΔ51M in various models including resistant cancer cell lines, murine tumor biopsies, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. The strongest sensitizing effect to VSVΔ51M infection within the itaconate family is elucidated by 4-octyl itaconate (4-OI), a known activator of nuclear factor erythroid 2-related factor 2 (NRF2). Importantly, the sensitization to VSVΔ51M with 4-OI is not observed in non-cancer primary human cells, healthy mouse-derived tissues, and normal human colon organoids. Additionally, 4-OI improves the virus spread within a resistant mouse colon tumor model in vivo. Mechanistically, we found that the effect of 4-OI is not mediated by NRF2 or KEAP1. Instead, we show that 4-OI targets multiple pathways including the RIG-MAVS, the IKKβ-NF-κB and the JAK1-STAT1 pathways through the modification of cysteine residues in MAVS, IKKβ and JAK1, respectively. Here, 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
Publisher	Research Square 2023
Edition	1
Volume	Version
DOIs	https://doi.org/10.21203/rs.3.rs-3035315/v1
Publication status	Published - 8 Jun 2023

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Cite this

Kurmasheva, N., Said, A., Wong, B., Kress, A., Liu, Z., Wang, C., Carter-Timofte, M. E., Holm, E., van der Horst, D., Hoang, H.-D., Twayana, K. S., Ottosen, R., Svenningsen, E. B., Begnini, F., Kiib, A. E., Weiss, H., Di Carlo, D., Muscolini, M., Higgins, M., ... Olagnier, D. P. C. (2023). Itaconate enhances oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways. (1 ed.) Research Square 2023. https://doi.org/10.21203/rs.3.rs-3035315/v1

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title = "Itaconate enhances oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways",

abstract = "Altered metabolism and defective innate immune responses are hallmarks of tumor cells, creating a niche that can be exploited by viruses with oncolytic properties. However, heterogeneity in responses to oncolytic virotherapy is a barrier to clinical effectiveness. Resistance to oncolytic virotherapy exists and occurs via inhibition of viral spread within the tumor that may result in treatment failures. Here we show that the Krebs cycle-derived metabolite itaconate and its chemical derivatives or natural isomers enhance oncolytic virotherapy with VSVΔ51M in various models including resistant cancer cell lines, murine tumor biopsies, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. The strongest sensitizing effect to VSVΔ51M infection within the itaconate family is elucidated by 4-octyl itaconate (4-OI), a known activator of nuclear factor erythroid 2-related factor 2 (NRF2). Importantly, the sensitization to VSVΔ51M with 4-OI is not observed in non-cancer primary human cells, healthy mouse-derived tissues, and normal human colon organoids. Additionally, 4-OI improves the virus spread within a resistant mouse colon tumor model in vivo. Mechanistically, we found that the effect of 4-OI is not mediated by NRF2 or KEAP1. Instead, we show that 4-OI targets multiple pathways including the RIG-MAVS, the IKKβ-NF-κB and the JAK1-STAT1 pathways through the modification of cysteine residues in MAVS, IKKβ and JAK1, respectively. Here, 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.",

author = "Naziia Kurmasheva and Aida Said and Boaz Wong and Alena Kress and Zhenlong Liu and Chen Wang and Carter-Timofte, {Madalina Elena} and Emilia Holm and {van der Horst}, Demi and Huy-Dung Hoang and Twayana, {Krishna Sundar} and Rasmus Ottosen and Svenningsen, {Esben Bjerregaard} and Fabio Begnini and Kiib, {Anders Engsted} and Hauke Weiss and {Di Carlo}, Daniele and Michela Muscolini and Maureen Higgins and Priscilla Kinderman and {van der Heijden}, Mirte and Tong Tong and Attila Ozsvar and Wen-Hsien Hou and Vivien Schack and {Bach Holm}, Christian and {van Montfoort}, Nadine and Yunan Zheng and Melanie Ruzek and Kalucka, {Joanna Maria} and {de la Vega}, Laureano and Elgaher, {Walid A M} and Korshoej, {Anders Rosendal} and Rongtuan Lin and John Hiscottt and Thomas Poulsen and Luke O´Neill and Diallo, {Jean Simon} and Henner Farin and Tommy Alain and Olagnier, {David Pierre Christophe}",

year = "2023",

month = jun,

day = "8",

doi = "10.21203/rs.3.rs-3035315/v1",

language = "English",

volume = "Version",

publisher = "Research Square 2023",

edition = "1",

type = "WorkingPaper",

institution = "Research Square 2023",

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Kurmasheva, N, Said, A, Wong, B, Kress, A, Liu, Z, Wang, C, Carter-Timofte, ME, Holm, E, van der Horst, D, Hoang, H-D, Twayana, KS, Ottosen, R, Svenningsen, EB, Begnini, F, Kiib, AE, Weiss, H, Di Carlo, D, Muscolini, M, Higgins, M, Kinderman, P, van der Heijden, M, Tong, T, Ozsvar, A, Hou, W-H , Schack, V , Bach Holm, C, van Montfoort, N, Zheng, Y, Ruzek, M, Kalucka, JM, de la Vega, L, Elgaher, WAM, Korshoej, AR, Lin, R, Hiscottt, J, Poulsen, T, O´Neill, L, Diallo, JS, Farin, H, Alain, T & Olagnier, DPC 2023 'Itaconate enhances oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways' 1 edn, Research Square 2023. https://doi.org/10.21203/rs.3.rs-3035315/v1

TY - UNPB

T1 - Itaconate enhances oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

AU - Kurmasheva, Naziia

AU - Said, Aida

AU - Wong, Boaz

AU - Kress, Alena

AU - Liu, Zhenlong

AU - Wang, Chen

AU - Carter-Timofte, Madalina Elena

AU - Holm, Emilia

AU - van der Horst, Demi

AU - Hoang, Huy-Dung

AU - Twayana, Krishna Sundar

AU - Ottosen, Rasmus

AU - Svenningsen, Esben Bjerregaard

AU - Begnini, Fabio

AU - Kiib, Anders Engsted

AU - Weiss, Hauke

AU - Di Carlo, Daniele

AU - Muscolini, Michela

AU - Higgins, Maureen

AU - Kinderman, Priscilla

AU - van der Heijden, Mirte

AU - Tong, Tong

AU - Ozsvar, Attila

AU - Hou, Wen-Hsien

AU - Schack, Vivien

AU - Bach Holm, Christian

AU - van Montfoort, Nadine

AU - Zheng, Yunan

AU - Ruzek, Melanie

AU - Kalucka, Joanna Maria

AU - de la Vega, Laureano

AU - Elgaher, Walid A M

AU - Korshoej, Anders Rosendal

AU - Lin, Rongtuan

AU - Hiscottt, John

AU - Poulsen, Thomas

AU - O´Neill, Luke

AU - Diallo, Jean Simon

AU - Farin, Henner

AU - Alain, Tommy

AU - Olagnier, David Pierre Christophe

PY - 2023/6/8

Y1 - 2023/6/8

N2 - Altered metabolism and defective innate immune responses are hallmarks of tumor cells, creating a niche that can be exploited by viruses with oncolytic properties. However, heterogeneity in responses to oncolytic virotherapy is a barrier to clinical effectiveness. Resistance to oncolytic virotherapy exists and occurs via inhibition of viral spread within the tumor that may result in treatment failures. Here we show that the Krebs cycle-derived metabolite itaconate and its chemical derivatives or natural isomers enhance oncolytic virotherapy with VSVΔ51M in various models including resistant cancer cell lines, murine tumor biopsies, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. The strongest sensitizing effect to VSVΔ51M infection within the itaconate family is elucidated by 4-octyl itaconate (4-OI), a known activator of nuclear factor erythroid 2-related factor 2 (NRF2). Importantly, the sensitization to VSVΔ51M with 4-OI is not observed in non-cancer primary human cells, healthy mouse-derived tissues, and normal human colon organoids. Additionally, 4-OI improves the virus spread within a resistant mouse colon tumor model in vivo. Mechanistically, we found that the effect of 4-OI is not mediated by NRF2 or KEAP1. Instead, we show that 4-OI targets multiple pathways including the RIG-MAVS, the IKKβ-NF-κB and the JAK1-STAT1 pathways through the modification of cysteine residues in MAVS, IKKβ and JAK1, respectively. Here, 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 - Altered metabolism and defective innate immune responses are hallmarks of tumor cells, creating a niche that can be exploited by viruses with oncolytic properties. However, heterogeneity in responses to oncolytic virotherapy is a barrier to clinical effectiveness. Resistance to oncolytic virotherapy exists and occurs via inhibition of viral spread within the tumor that may result in treatment failures. Here we show that the Krebs cycle-derived metabolite itaconate and its chemical derivatives or natural isomers enhance oncolytic virotherapy with VSVΔ51M in various models including resistant cancer cell lines, murine tumor biopsies, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. The strongest sensitizing effect to VSVΔ51M infection within the itaconate family is elucidated by 4-octyl itaconate (4-OI), a known activator of nuclear factor erythroid 2-related factor 2 (NRF2). Importantly, the sensitization to VSVΔ51M with 4-OI is not observed in non-cancer primary human cells, healthy mouse-derived tissues, and normal human colon organoids. Additionally, 4-OI improves the virus spread within a resistant mouse colon tumor model in vivo. Mechanistically, we found that the effect of 4-OI is not mediated by NRF2 or KEAP1. Instead, we show that 4-OI targets multiple pathways including the RIG-MAVS, the IKKβ-NF-κB and the JAK1-STAT1 pathways through the modification of cysteine residues in MAVS, IKKβ and JAK1, respectively. Here, 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.

U2 - 10.21203/rs.3.rs-3035315/v1

DO - 10.21203/rs.3.rs-3035315/v1

M3 - Preprint

VL - Version

BT - Itaconate enhances oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

PB - Research Square 2023

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