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

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posted on 2021-01-01, 00:00 authored by M C Brown, M M Mosaheb, M Mohme, Z P McKay, E K Holl, J P Kastan, Y Yang, G M Beasley, E S Hwang, David Ashley, D D Bigner, S K Nair, M Gromeier
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.

History

Journal

Nature communications

Volume

12

Issue

1

Article number

1858

Pagination

1 - 16

Publisher

Nature Publishing Group

Location

London, Eng.

ISSN

2041-1723

eISSN

2041-1723

Language

English

Publication classification

C1 Refereed article in a scholarly journal

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