IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma

Masaya Aoki; Licun Wu; Junichi Murakami; Yidan Zhao; Hana Yun; Marc de Perrot

doi:10.3390/jcm10215196

IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma

J Clin Med. 2021 Nov 7;10(21):5196. doi: 10.3390/jcm10215196.

Authors

Masaya Aoki¹, Licun Wu¹, Junichi Murakami¹, Yidan Zhao¹, Hana Yun¹, Marc de Perrot^{1

2

3}

Affiliations

¹ Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Princess Margaret Cancer Research Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada.
² Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
³ Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.

Abstract

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⁺ T cells and CD8⁺IFNγ⁺ T cells were significantly increased. TCGA data showed that IRF3 expression was an unfavorable prognostic factor in MESO patients. IRF3 expression, the cGAS/STING signaling pathway, and immune checkpoints were positively correlated.

Conclusion: IRF3 could play a critical role in the tumor immune microenvironment of MESO.

Keywords: IRF3 knockout (IRF3KO); cGAS/STING signaling pathway; immune checkpoints; interferon regulatory factor 3 (IRF3); malignant pleural mesothelioma (MESO).