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Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling

Brown, Michael C, Mosaheb, Mubeen M, Mohme, Malte, McKay, Zachary P, Holl, Eda K, Kastan, Jonathan P, Yang, Yuanfan, Beasley, Georgia M, Hwang, E Shelley, Ashley, David M, Bigner, Darell D, Nair, Smita K and Gromeier, Matthias 2021, Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling, Nature communications, vol. 12, no. 1, pp. 1-16, doi: 10.1038/s41467-021-22088-1.

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Title Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling
Author(s) Brown, Michael C
Mosaheb, Mubeen M
Mohme, Malte
McKay, Zachary P
Holl, Eda K
Kastan, Jonathan P
Yang, Yuanfan
Beasley, Georgia M
Hwang, E Shelley
Ashley, David M
Bigner, Darell D
Nair, Smita K
Gromeier, Matthias
Journal name Nature communications
Volume number 12
Issue number 1
Article ID 1858
Start page 1
End page 16
Total pages 16
Publisher Nature Publishing Group
Place of publication London, Eng.
Publication date 2021
ISSN 2041-1723
2041-1723
Keyword(s) cancer therapy
immunotherapy
tumour immunology
Multidisciplinary Sciences
Science & Technology
Summary Abstract Activating intra-tumor innate immunity might enhance tumor immune surveillance. Virotherapy is proposed to achieve tumor cell killing, while indirectly activating innate immunity. Here, we report that recombinant poliovirus therapy primarily mediates antitumor immunotherapy via direct infection of non-malignant tumor microenvironment (TME) cells, independent of malignant cell lysis. Relative to other innate immune agonists, virotherapy provokes selective, TBK1-IRF3 driven innate inflammation that is associated with sustained type-I/III interferon (IFN) release. Despite priming equivalent antitumor T cell quantities, MDA5-orchestrated TBK1-IRF3 signaling, but not NFκB-polarized TLR activation, culminates in polyfunctional and Th1-differentiated antitumor T cell phenotypes. Recombinant type-I IFN increases tumor-localized T cell function, but does not mediate durable antitumor immunotherapy without concomitant pattern recognition receptor (PRR) signaling. Thus, virus-induced MDA5-TBK1-IRF3 signaling in the TME provides PRR-contextualized IFN responses that elicit functional antitumor T cell immunity. TBK1-IRF3 innate signal transduction stimulates eventual function and differentiation of tumor-infiltrating T cells.
Language eng
DOI 10.1038/s41467-021-22088-1
Indigenous content off
HERDC Research category C1 Refereed article in a scholarly journal
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30150065

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.