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

Publication ,  Journal Article
Brown, MC; Mosaheb, MM; Mohme, M; McKay, ZP; Holl, EK; Kastan, JP; Yang, Y; Beasley, GM; Hwang, ES; Ashley, DM; Bigner, DD; Nair, SK; Gromeier, M
Published in: Nat Commun
March 25, 2021

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.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

March 25, 2021

Volume

12

Issue

1

Start / End Page

1858

Location

England

Related Subject Headings

  • Tumor Microenvironment
  • Th1 Cells
  • Signal Transduction
  • Protein Serine-Threonine Kinases
  • Oncolytic Virotherapy
  • NF-kappa B
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Melanoma
 

Citation

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Brown, M. C., Mosaheb, M. M., Mohme, M., McKay, Z. P., Holl, E. K., Kastan, J. P., … Gromeier, M. (2021). Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling. Nat Commun, 12(1), 1858. https://doi.org/10.1038/s41467-021-22088-1
Brown, Michael C., Mubeen M. Mosaheb, Malte Mohme, Zachary P. McKay, Eda K. Holl, Jonathan P. Kastan, Yuanfan Yang, et al. “Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling.Nat Commun 12, no. 1 (March 25, 2021): 1858. https://doi.org/10.1038/s41467-021-22088-1.
Brown MC, Mosaheb MM, Mohme M, McKay ZP, Holl EK, Kastan JP, et al. Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling. Nat Commun. 2021 Mar 25;12(1):1858.
Brown, Michael C., et al. “Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling.Nat Commun, vol. 12, no. 1, Mar. 2021, p. 1858. Pubmed, doi:10.1038/s41467-021-22088-1.
Brown MC, Mosaheb MM, Mohme M, McKay ZP, Holl EK, Kastan JP, Yang Y, Beasley GM, Hwang ES, Ashley DM, Bigner DD, Nair SK, Gromeier M. Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling. Nat Commun. 2021 Mar 25;12(1):1858.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

March 25, 2021

Volume

12

Issue

1

Start / End Page

1858

Location

England

Related Subject Headings

  • Tumor Microenvironment
  • Th1 Cells
  • Signal Transduction
  • Protein Serine-Threonine Kinases
  • Oncolytic Virotherapy
  • NF-kappa B
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Melanoma