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

Michael C. Brown, Mubeen M. Mosaheb, Malte Mohme, Zachary P. McKay, Eda K. Holl, Jonathan P. Kastan, Yuanfan Yang, Georgia M. Beasley, E. Shelley Hwang, David M. Ashley, Darell D. Bigner, Smita K. Nair and Matthias Gromeier ()
Additional contact information
Michael C. Brown: Duke University Medical School
Mubeen M. Mosaheb: Duke University Medical School
Malte Mohme: University of Hamburg Medical Center
Zachary P. McKay: Duke University Medical School
Eda K. Holl: Duke University Medical School
Jonathan P. Kastan: Duke University
Yuanfan Yang: Duke University Medical School
Georgia M. Beasley: Duke University Medical School
E. Shelley Hwang: Duke University Medical School
David M. Ashley: Duke University Medical School
Darell D. Bigner: Duke University Medical School
Smita K. Nair: Duke University Medical School
Matthias Gromeier: Duke University Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-22088-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22088-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-22088-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().