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Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling
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Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling
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Journal Article
Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling
2021
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/21
/ 13/31
/ 64/110
/ 64/60
/ 82/29
/ Animals
/ Breast Neoplasms - immunology
/ Breast Neoplasms - pathology
/ CD8-Positive T-Lymphocytes - immunology
/ Female
/ Humanities and Social Sciences
/ Humans
/ Immunity
/ Immunity, Innate - immunology
/ Interferon regulatory factor 3
/ Interferon Regulatory Factor-3 - immunology
/ Interferon Type I - immunology
/ Interferon-Induced Helicase, IFIH1 - metabolism
/ Lymphocytes, Tumor-Infiltrating - immunology
/ Lysis
/ Mice
/ Pattern recognition receptors
/ Priming
/ Protein Serine-Threonine Kinases - immunology
/ Science
/ Signal Transduction - immunology
/ Tumor Microenvironment - immunology
/ Tumor-infiltrating lymphocytes
/ Tumors
