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- Title
Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling.
- Authors
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
- 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. Innate intratumoral immunity might be important in enhancing oncolytic tumor immunotherapy. Here, the authors show that recombinant poliovirus signalling through TBK-IRF3 enhances tumor-infiltrating T cell activity and multi-cytokine function.
- Subjects
VIRUS diseases; TUMOR microenvironment; CANCER cells; PATTERN perception receptors; T cell differentiation; INTERFERON receptors
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-22088-1