IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma

Background: Malignant pleural mesothelioma (MESO) has a poor prognosis despite aggressive treatment with surgery, radiation and chemotherapy, and novel therapeutic approaches are needed. IRF3 is a downstream molecule of the cGAS/STING signaling pathway, but its roles have not been investigated in ME...

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Autores principales:	Masaya Aoki, Licun Wu, Junichi Murakami, Yidan Zhao, Hana Yun, Marc de Perrot
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	malignant pleural mesothelioma (MESO) interferon regulatory factor 3 (IRF3) cGAS/STING signaling pathway IRF3 knockout (IRF3KO) immune checkpoints Medicine R
Acceso en línea:	https://doaj.org/article/5f605b1bd0c94dbb8682ab437b585836
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spelling	oai:doaj.org-article:5f605b1bd0c94dbb8682ab437b5858362021-11-11T17:48:04ZIRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma10.3390/jcm102151962077-0383https://doaj.org/article/5f605b1bd0c94dbb8682ab437b5858362021-11-01T00:00:00Zhttps://www.mdpi.com/2077-0383/10/21/5196https://doaj.org/toc/2077-0383Background: Malignant pleural mesothelioma (MESO) has a poor prognosis despite aggressive treatment with surgery, radiation and chemotherapy, and novel therapeutic approaches are needed. IRF3 is a downstream molecule of the cGAS/STING signaling pathway, but its roles have not been investigated in MESO. Methods: Various murine mesothelioma cell lines were inoculated into wild type (WT) and IRF3 knockout (IRF3KO) mice to compare tumor growth. AE17-bearing mice were treated with local radiotherapy (LRT) to evaluate the effect on tumor growth, and immune cell infiltration was analyzed by flow cytometry 20 days after tumor inoculation. TCGA data were used to examine the relationship between mRNA expression of IRF3 and genes of the cGAS/STING signaling cascade on prognosis in MESO. Correlations between gene expression of IRF3, cGAS/STING signaling pathway, and immune checkpoints were analyzed in TCGA MESO and our scRNA-Seq data from MESO patients. Results: In mouse mesothelioma models, AK7, RN5 and ZiP3 were completely rejected in IRF3KO mice 20 days after the tumor challenge. AE17tumor volume was slightly larger than WT mice around day 10 before shrinking and becoming significantly smaller than WT mice on day 20. LRT accelerated tumor shrinkage of AE17 tumors in IRF3KO mice. Compared with WT mice, the number of macrophages infiltrating the tumor of IRF3KO mice was significantly reduced, and CD4<sup>+</sup> T cells and CD8<sup>+</sup>IFNγ<sup>+</sup> T cells were significantly increased. TCGA data showed that <i>IRF3</i> expression was an unfavorable prognostic factor in MESO patients. <i>IRF3</i> expression, the cGAS/STING signaling pathway, and immune checkpoints were positively correlated. Conclusion: <i>IRF3</i> could play a critical role in the tumor immune microenvironment of MESO.Masaya AokiLicun WuJunichi MurakamiYidan ZhaoHana YunMarc de PerrotMDPI AGarticlemalignant pleural mesothelioma (MESO)interferon regulatory factor 3 (IRF3)cGAS/STING signaling pathwayIRF3 knockout (IRF3KO)immune checkpointsMedicineRENJournal of Clinical Medicine, Vol 10, Iss 5196, p 5196 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	malignant pleural mesothelioma (MESO) interferon regulatory factor 3 (IRF3) cGAS/STING signaling pathway IRF3 knockout (IRF3KO) immune checkpoints Medicine R
spellingShingle	malignant pleural mesothelioma (MESO) interferon regulatory factor 3 (IRF3) cGAS/STING signaling pathway IRF3 knockout (IRF3KO) immune checkpoints Medicine R Masaya Aoki Licun Wu Junichi Murakami Yidan Zhao Hana Yun Marc de Perrot IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma
description	Background: Malignant pleural mesothelioma (MESO) has a poor prognosis despite aggressive treatment with surgery, radiation and chemotherapy, and novel therapeutic approaches are needed. IRF3 is a downstream molecule of the cGAS/STING signaling pathway, but its roles have not been investigated in MESO. Methods: Various murine mesothelioma cell lines were inoculated into wild type (WT) and IRF3 knockout (IRF3KO) mice to compare tumor growth. AE17-bearing mice were treated with local radiotherapy (LRT) to evaluate the effect on tumor growth, and immune cell infiltration was analyzed by flow cytometry 20 days after tumor inoculation. TCGA data were used to examine the relationship between mRNA expression of IRF3 and genes of the cGAS/STING signaling cascade on prognosis in MESO. Correlations between gene expression of IRF3, cGAS/STING signaling pathway, and immune checkpoints were analyzed in TCGA MESO and our scRNA-Seq data from MESO patients. Results: In mouse mesothelioma models, AK7, RN5 and ZiP3 were completely rejected in IRF3KO mice 20 days after the tumor challenge. AE17tumor volume was slightly larger than WT mice around day 10 before shrinking and becoming significantly smaller than WT mice on day 20. LRT accelerated tumor shrinkage of AE17 tumors in IRF3KO mice. Compared with WT mice, the number of macrophages infiltrating the tumor of IRF3KO mice was significantly reduced, and CD4<sup>+</sup> T cells and CD8<sup>+</sup>IFNγ<sup>+</sup> T cells were significantly increased. TCGA data showed that <i>IRF3</i> expression was an unfavorable prognostic factor in MESO patients. <i>IRF3</i> expression, the cGAS/STING signaling pathway, and immune checkpoints were positively correlated. Conclusion: <i>IRF3</i> could play a critical role in the tumor immune microenvironment of MESO.
format	article
author	Masaya Aoki Licun Wu Junichi Murakami Yidan Zhao Hana Yun Marc de Perrot
author_facet	Masaya Aoki Licun Wu Junichi Murakami Yidan Zhao Hana Yun Marc de Perrot
author_sort	Masaya Aoki
title	IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma
title_short	IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma
title_full	IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma
title_fullStr	IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma
title_full_unstemmed	IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma
title_sort	irf3 knockout results in partial or complete rejection of murine mesothelioma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5f605b1bd0c94dbb8682ab437b585836
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_version_	1718432003187015680

IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma

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