IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma

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.

Isolated BAP1 Genomic Alteration in Malignant Pleural Mesothelioma Predicts Distinct Immunogenicity with Implications for Immunotherapeutic Response

“…Regarding possible future validation experiments to confirm the tumor-promoting roles of IRF TFs and interferon signaling in B∆ MPM, expression levels of IRF TFs can be manipulated in cultured cells through overexpression or silencing, and the effects of IRF TFs on cancer cell proliferation, survival, motility, and invasion potential can then be evaluated. Ultimately, in vivo validation of the roles of IRF TFs expression on MPM progression can be studied using mouse models of mesothelioma crossed with mice harboring knockout of specific IRF TF genes [ 33 ].…”

Octadecyl Gallate and Lipid‐Modified MnSe2 Nanoparticles Enhance Radiosensitivity in Esophageal Squamous Cell Carcinoma and Promote Radioprotection in Normal Tissues

“…[ 17,18 ] Occasionally, a solitary gene may be insufficient for discerning the prognosis of patients. [ 19 ] To overcome this limitation and investigate the influence of the cGAS‐STING pathway on radiotherapy, we sought to develop a prognostic signature based on four core genes (cGAS, STING, TBK1, and IRF3) of cGAS‐STING pathway by analyzing the transcriptome data of tumor tissues derived from cervical squamous cell carcinoma (CSCC, n = 109), head and neck squamous cell carcinoma (HNSCC, n = 252), and ESCC ( n = 36), with which patients received radiotherapy. As expected, we found that OS is significantly longer in patients with high CS score than those with low CS score ( Figure A–C).…”