Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma

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Abstract

Oncolytic virotherapy holds promise for cancer treatment, but the factors determining its oncolytic activity remain unclear. Neutrophil extracellular traps (NETs) are associated with cancer progression, yet their formation mechanism and role in oncolytic virotherapy remain elusive. In this study, we demonstrate that, in glioma, upregulation of IGF2BP3 enhances the expression of E3 ubiquitin protein ligase MIB1, promoting FTO degradation via the ubiquitin-proteasome pathway. This results in increased m6A-mediated CSF3 release and NET formation. Oncolytic herpes simplex virus (oHSV) stimulates IGF2BP3-induced NET formation in malignant glioma. In glioma models in female mice, a BET inhibitor enhances the oncolytic activity of oHSV by impeding IGF2BP3-induced NETosis, reinforcing virus replication through BRD4 recruitment with the CDK9/RPB-1 complex to HSV gene promoters. Our findings unveil the regulation of m6A-mediated NET formation, highlight oncolytic virus-induced NETosis as a critical checkpoint hindering oncolytic potential, and propose targeting NETosis as a strategy to overcome resistance in oncolytic virotherapy.

Abstract

The m6A reader IGF2BP3 is upregulated in various cancer, including glioblastoma. Here the authors report that IGF2BP3 facilitates NETosis and glioma survival as well as resistance to oncolytic herpes simplex virotherapy.

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Neutrophil extracellular traps kill bacteria.

V Brinkmann (2004)

Neutrophils engulf and kill bacteria when their antimicrobial granules fuse with the phagosome. Here, we describe that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria. These neutrophil extracellular traps (NETs) degrade virulence factors and kill bacteria. NETs are abundant in vivo in experimental dysentery and spontaneous human appendicitis, two examples of acute inflammation. NETs appear to be a form of innate response that binds microorganisms, prevents them from spreading, and ensures a high local concentration of antimicrobial agents to degrade virulence factors and kill bacteria.

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Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer.

Gabriela Bindea, Bernhard Mlecnik, Marie Tosolini … (2013)

The complex interactions between tumors and their microenvironment remain to be elucidated. Combining large-scale approaches, we examined the spatio-temporal dynamics of 28 different immune cell types (immunome) infiltrating tumors. We found that the immune infiltrate composition changed at each tumor stage and that particular cells had a major impact on survival. Densities of T follicular helper (Tfh) cells and innate cells increased, whereas most T cell densities decreased along with tumor progression. The number of B cells, which are key players in the core immune network and are associated with prolonged survival, increased at a late stage and showed a dual effect on recurrence and tumor progression. The immune control relevance was demonstrated in three endoscopic orthotopic colon-cancer mouse models. Genomic instability of the chemokine CXCL13 was a mechanism associated with Tfh and B cell infiltration. CXCL13 and IL21 were pivotal factors for the Tfh/B cell axis correlating with survival. This integrative study reveals the immune landscape in human colorectal cancer and the major hallmarks of the microenvironment associated with tumor progression and recurrence. Copyright © 2013 Elsevier Inc. All rights reserved.

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Recognition of RNA N 6 -methyladenosine by IGF2BP Proteins Enhances mRNA Stability and Translation

Huilin Huang, Hengyou Weng, Wenju Sun … (2018)

N 6-methyladenosine (m6A) is the most prevalent modification in eukaryotic messenger RNAs (mRNAs) and is interpreted by its readers, such as YTH domain-containing proteins, to regulate mRNA fate. Here we report the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1/2/3) as a distinct family of m6A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m6A)C sequence. In contrast to the mRNA-decay-promoting function of YTHDF2, IGF2BPs promote the stability and storage of their target mRNAs (e.g., MYC) in an m6A-depedent manner under normal and stress conditions and thus affect gene expression output. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A and are critical for their oncogenic functions. Our work therefore reveals a different facet of the m6A-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as m6A readers in post-transcriptional gene regulation and cancer biology.

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Author and article information

Contributors

Juxiang Chen: juxiangchen@smmu.edu.cn

Minfeng Shu:

ORCID: http://orcid.org/0000-0003-0514-1892

minfeng_shu@fudan.edu.cn

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 2 January 2024

Publication date PMC-release: 2 January 2024

Publication date Collection: 2024

Volume: 15

Electronic Location Identifier: 131

Affiliations

[1 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, , Fudan University, ; Shanghai, China

[2 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, , Fudan University, ; Shanghai, China

[3 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Department of Interventional Radiology, Zhongshan hospital, , Fudan University, ; Shanghai, China

[4 ]School of Basic Medical Sciences, Fudan University, ( https://ror.org/013q1eq08) Shanghai, China

[5 ]Nanhu Laboratory, National Center of Biomedical Analysis, ( https://ror.org/03k3bq214) Beijing, China

[6 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Department of Pathology, Zhongshan hospital, , Fudan University, ; Shanghai, China

[7 ]Department of Neurosurgery, Shanghai Changhai Hospital, Naval Medical University, ( https://ror.org/02bjs0p66) Shanghai, China

Author information

Shasha Bian http://orcid.org/0000-0002-7095-0867

Xin Pan http://orcid.org/0000-0002-1982-2261

Minfeng Shu http://orcid.org/0000-0003-0514-1892

Article

Publisher ID: 44576

DOI: 10.1038/s41467-023-44576-2

PMC ID: 10762148

PubMed ID: 38167409

SO-VID: 91868516-746d-44cc-85a6-2eec832ce04c

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 22 June 2023

Date accepted : 20 December 2023

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: No. 81872467 and 82073880

Award Recipient : Minfeng Shu

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ScienceOpen disciplines: Uncategorized

Keywords: cns cancer,cancer immunotherapy,herpes virus

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ScienceOpen disciplines: Uncategorized

Keywords: cns cancer, cancer immunotherapy, herpes virus

Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma

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Cancer Immunotherapy

Most cited references 41

Neutrophil extracellular traps kill bacteria.

Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer.

Recognition of RNA N 6 -methyladenosine by IGF2BP Proteins Enhances mRNA Stability and Translation

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