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Updated: Oct 13, 2025
Orthotopic Implantation and Peripheral Immune Cell Monitoring in the II-45 Syngeneic Rat Mesothelioma Model
Published on: October 2, 2015
IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma
Masaya Aoki1, Licun Wu1, Junichi Murakami1
1Latner 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.
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.
Insights
Interferon regulatory factor 3 (IRF3) plays a key role in malignant pleural mesothelioma (MESO) tumor immunity. Its absence hinders tumor growth and alters immune cell infiltration, suggesting therapeutic potential for MESO treatment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Malignant pleural mesothelioma (MESO) has a poor prognosis, necessitating novel therapeutic strategies.
- The role of Interferon regulatory factor 3 (IRF3), a cGAS/STING pathway molecule, in MESO remains unexplored.
Purpose of the Study:
- To investigate the role of IRF3 in MESO tumor growth and the tumor immune microenvironment.
- To explore the correlation between IRF3, cGAS/STING signaling, and immune checkpoints in MESO patients.
Main Methods:
- Murine mesothelioma models (WT and IRF3 knockout mice) were used to assess tumor growth.
- Local radiotherapy (LRT) effects and immune cell infiltration were analyzed via flow cytometry.
- TCGA and scRNA-Seq data were utilized to examine IRF3 expression, cGAS/STING pathway, and immune checkpoint correlations.
Main Results:
- IRF3 knockout mice exhibited complete tumor rejection or significantly reduced tumor volume compared to WT mice.
- IRF3 deficiency led to decreased macrophage infiltration and increased CD4+ and CD8+ T cell infiltration.
- TCGA data indicated IRF3 expression is an unfavorable prognostic factor and positively correlates with cGAS/STING pathway and immune checkpoints in MESO.
Conclusions:
- IRF3 plays a critical role in the tumor immune microenvironment of MESO.
- Targeting IRF3 may represent a novel therapeutic strategy for MESO.
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