IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma

Overview

Journal J Clin Med

Specialty General Medicine

Date 2021 Nov 13

PMID 34768716

Citations 3

Authors

Masaya Aoki

Licun Wu

Junichi Murakami

Yidan Zhao

Hana Yun

Marc de Perrot

Affiliations

Soon will be listed here.

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 CD8IFNγ T cells were significantly increased. TCGA data showed that expression was an unfavorable prognostic factor in MESO patients. expression, the cGAS/STING signaling pathway, and immune checkpoints were positively correlated.

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

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References

Yang S, Lheureux S, Karakasis K, Burnier J, Bruce J, Clouthier D . Landscape of genomic alterations in high-grade serous ovarian cancer from exceptional long- and short-term survivors. Genome Med. 2018; 10(1):81. PMC: 6208125. DOI: 10.1186/s13073-018-0590-x. View

DeNardo D, Brennan D, Rexhepaj E, Ruffell B, Shiao S, Madden S . Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011; 1(1):54-67. PMC: 3203524. DOI: 10.1158/2159-8274.CD-10-0028. View

Mereiter S, Balmana M, Campos D, Gomes J, Reis C . Glycosylation in the Era of Cancer-Targeted Therapy: Where Are We Heading?. Cancer Cell. 2019; 36(1):6-16. DOI: 10.1016/j.ccell.2019.06.006. View

Tian M, Wang X, Sun J, Lin W, Chen L, Liu S . IRF3 prevents colorectal tumorigenesis via inhibiting the nuclear translocation of β-catenin. Nat Commun. 2020; 11(1):5762. PMC: 7666182. DOI: 10.1038/s41467-020-19627-7. View

Rodriguez E, Schetters S, van Kooyk Y . The tumour glyco-code as a novel immune checkpoint for immunotherapy. Nat Rev Immunol. 2018; 18(3):204-211. DOI: 10.1038/nri.2018.3. View

Cho B, Feld R, Leighl N, Opitz I, Anraku M, Tsao M . A feasibility study evaluating Surgery for Mesothelioma After Radiation Therapy: the "SMART" approach for resectable malignant pleural mesothelioma. J Thorac Oncol. 2014; 9(3):397-402. DOI: 10.1097/JTO.0000000000000078. View

Cagnoni A, Giribaldi M, Blidner A, Cutine A, Gatto S, Morales R . Galectin-1 fosters an immunosuppressive microenvironment in colorectal cancer by reprogramming CD8 regulatory T cells. Proc Natl Acad Sci U S A. 2021; 118(21). PMC: 8166155. DOI: 10.1073/pnas.2102950118. View

An X, Zhu Y, Zheng T, Wang G, Zhang M, Li J . An Analysis of the Expression and Association with Immune Cell Infiltration of the cGAS/STING Pathway in Pan-Cancer. Mol Ther Nucleic Acids. 2018; 14:80-89. PMC: 6305687. DOI: 10.1016/j.omtn.2018.11.003. View

Ran Y, Shu H, Wang Y . MITA/STING: a central and multifaceted mediator in innate immune response. Cytokine Growth Factor Rev. 2014; 25(6):631-9. PMC: 7108248. DOI: 10.1016/j.cytogfr.2014.05.003. View

10.

de la Maza L, Wu M, Wu L, Yun H, Zhao Y, Cattral M . Vaccination after Accelerated Hypofractionated Radiation and Surgery in a Mesothelioma Mouse Model. Clin Cancer Res. 2017; 23(18):5502-5513. DOI: 10.1158/1078-0432.CCR-17-0438. View

11.

Rusch V, Piantadosi S, Holmes E . The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A Lung Cancer Study Group trial. J Thorac Cardiovasc Surg. 1991; 102(1):1-9. View

12.

Zhu C, Li J, Yao M, Fang C . Potential for treatment benefit of STING agonists plus immune checkpoint inhibitors in oral squamous cell carcinoma. BMC Oral Health. 2021; 21(1):506. PMC: 8501566. DOI: 10.1186/s12903-021-01813-8. View

13.

Cho B, Donahoe L, Bradbury P, Leighl N, Keshavjee S, Hope A . Surgery for malignant pleural mesothelioma after radiotherapy (SMART): final results from a single-centre, phase 2 trial. Lancet Oncol. 2021; 22(2):190-197. DOI: 10.1016/S1470-2045(20)30606-9. View

14.

Pass H, Kranda K, Temeck B, Feuerstein I, Steinberg S . Surgically debulked malignant pleural mesothelioma: results and prognostic factors. Ann Surg Oncol. 1997; 4(3):215-22. DOI: 10.1007/BF02306613. View

15.

Heipertz E, Harper J, Goswami D, Lopez C, Nellikappallil J, Zamora R . IRF3 Signaling within the Mouse Stroma Influences Sepsis Pathogenesis. J Immunol. 2020; 206(2):398-409. PMC: 7785686. DOI: 10.4049/jimmunol.1900217. View

16.

Daguenet E, Louati S, Wozny A, Vial N, Gras M, Guy J . Radiation-induced bystander and abscopal effects: important lessons from preclinical models. Br J Cancer. 2020; 123(3):339-348. PMC: 7403362. DOI: 10.1038/s41416-020-0942-3. View

17.

Rusch V, Rosenzweig K, Venkatraman E, Leon L, Raben A, Harrison L . A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2001; 122(4):788-95. DOI: 10.1067/mtc.2001.116560. View

18.

Popat S, Curioni-Fontecedro A, Dafni U, Shah R, OBrien M, Pope A . A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial. Ann Oncol. 2020; 31(12):1734-1745. DOI: 10.1016/j.annonc.2020.09.009. View

19.

Decout A, Katz J, Venkatraman S, Ablasser A . The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021; 21(9):548-569. PMC: 8029610. DOI: 10.1038/s41577-021-00524-z. View

20.

Van Schil P, Baas P, Gaafar R, Maat A, van de Pol M, Hasan B . Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. Eur Respir J. 2010; 36(6):1362-9. DOI: 10.1183/09031936.00039510. View