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

Standard

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

in: NAT COMMUN, Jahrgang 12, Nr. 1, 25.03.2021, S. 1858.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

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 2021, 'Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling', NAT COMMUN, Jg. 12, Nr. 1, S. 1858. https://doi.org/10.1038/s41467-021-22088-1

APA

Brown, M. C., Mosaheb, M. M., Mohme, M., McKay, Z. P., Holl, E. K., Kastan, J. P., Yang, Y., Beasley, G. M., Hwang, E. S., Ashley, D. M., Bigner, D. D., Nair, S. K., & 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

Vancouver

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 Mär 25;12(1):1858. https://doi.org/10.1038/s41467-021-22088-1

Bibtex

@article{8b10fe2f6e034648a3e11feff59393bf,
title = "Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling",
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.",
keywords = "Animals, Breast Neoplasms/immunology, CD8-Positive T-Lymphocytes/immunology, Female, Humans, Immunity, Innate/immunology, Interferon Regulatory Factor-3/immunology, Interferon Type I/immunology, Interferon-Induced Helicase, IFIH1/metabolism, Lymphocytes, Tumor-Infiltrating/immunology, Melanoma/immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B/metabolism, Oncolytic Virotherapy, Protein Serine-Threonine Kinases/immunology, Signal Transduction/immunology, Th1 Cells/immunology, Tumor Microenvironment/immunology",
author = "Brown, {Michael C} and Mosaheb, {Mubeen M} and Malte Mohme and McKay, {Zachary P} and Holl, {Eda K} and Kastan, {Jonathan P} and Yuanfan Yang and Beasley, {Georgia M} and Hwang, {E Shelley} and Ashley, {David M} and Bigner, {Darell D} and Nair, {Smita K} and Matthias Gromeier",
year = "2021",
month = mar,
day = "25",
doi = "10.1038/s41467-021-22088-1",
language = "English",
volume = "12",
pages = "1858",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

TY - JOUR

T1 - Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling

AU - Brown, Michael C

AU - Mosaheb, Mubeen M

AU - Mohme, Malte

AU - McKay, Zachary P

AU - Holl, Eda K

AU - Kastan, Jonathan P

AU - Yang, Yuanfan

AU - Beasley, Georgia M

AU - Hwang, E Shelley

AU - Ashley, David M

AU - Bigner, Darell D

AU - Nair, Smita K

AU - Gromeier, Matthias

PY - 2021/3/25

Y1 - 2021/3/25

N2 - 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.

AB - 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.

KW - Animals

KW - Breast Neoplasms/immunology

KW - CD8-Positive T-Lymphocytes/immunology

KW - Female

KW - Humans

KW - Immunity, Innate/immunology

KW - Interferon Regulatory Factor-3/immunology

KW - Interferon Type I/immunology

KW - Interferon-Induced Helicase, IFIH1/metabolism

KW - Lymphocytes, Tumor-Infiltrating/immunology

KW - Melanoma/immunology

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - NF-kappa B/metabolism

KW - Oncolytic Virotherapy

KW - Protein Serine-Threonine Kinases/immunology

KW - Signal Transduction/immunology

KW - Th1 Cells/immunology

KW - Tumor Microenvironment/immunology

U2 - 10.1038/s41467-021-22088-1

DO - 10.1038/s41467-021-22088-1

M3 - SCORING: Journal article

C2 - 33767151

VL - 12

SP - 1858

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

ER -