Anti-triple-negative Breast Cancer Metastasis Efficacy and Molecular Mechanism of the STING Agonist for Innate Immune Pathway

Overview

Journal Ann Med

Publisher Informa Healthcare

Specialty General Medicine

Date 2023 May 10

PMID 37162544

Authors

Xing Lu

Xiang Wang

Hao Cheng

Xiaoqing Wang

Chang Liu

Xiangshi Tan

Affiliations

Soon will be listed here.

Abstract

Background: With high recurrence and metastatic rates, triple-negative breast cancer (TNBC) has few therapy choices. The innate immune stimulator of interferon genes protein (STING) pathway has emerged as a critical foundation for improving anticancer immunotherapy. Although 2',3'-cGAMP has been shown to have therapeutic potential as a STING agonist in subcutaneous solid tumour treatments in mice, the effect of cGAMP in metastatic malignancies has received less attention.

Methods: Bioluminescence imaging technology was applied to monitor TNBC tumour cell metastasis in living mice. Serum biochemical test and blood routine examination of mice were used to demonstrate cGAMP administration had no toxicity. The activation of DCs and CD8+ T cells was demonstrated by flow cytometry. The pharmacological mechanism of cGAMP for suppressing breast tumour metastasis was also explored.

Results: cGAMP treatment substantially suppressed tumour development and metastasis without adverse effects. cGAMP activated the cGAS-STING-IRF3 pathway, which modified the tumour immune milieu to reverse the Epithelial-Mesenchymal Transition (EMT) and PI3K/AKT pathways and prevent tumour metastasis. It was postulated and proven that cGAMP had a pharmacological mechanism for reducing breast tumour metastasis.

Conclusion: The findings suggest that cGAMP could be useful in the immunotherapy of immune-insensitive metastatic breast cancer.

Citing Articles

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References

Hartmann T, Burger M, Burger J . The role of adhesion molecules and chemokine receptor CXCR4 (CD184) in small cell lung cancer. J Biol Regul Homeost Agents. 2004; 18(2):126-30. View

Zhang S, Song X, He M, Yu S . Effect of TGF-β1/SDF-1/CXCR4 signal on BM-MSCs homing in rat heart of ischemia/perfusion injury. Eur Rev Med Pharmacol Sci. 2016; 20(5):899-905. View

Castanheira F, Kubes P . Neutrophils and NETs in modulating acute and chronic inflammation. Blood. 2019; 133(20):2178-2185. DOI: 10.1182/blood-2018-11-844530. View

Shu C, Yi G, Watts T, Kao C, Li P . Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system. Nat Struct Mol Biol. 2012; 19(7):722-4. PMC: 3392545. DOI: 10.1038/nsmb.2331. View

Skrnjug I, Guzman C, Rueckert C, Ruecker C . Cyclic GMP-AMP displays mucosal adjuvant activity in mice. PLoS One. 2014; 9(10):e110150. PMC: 4190368. DOI: 10.1371/journal.pone.0110150. View

Epstein R . The CXCL12-CXCR4 chemotactic pathway as a target of adjuvant breast cancer therapies. Nat Rev Cancer. 2004; 4(11):901-9. DOI: 10.1038/nrc1473. View

Welschinger R, Liedtke F, Basnett J, Dela Pena A, Juarez J, Bradstock K . Plerixafor (AMD3100) induces prolonged mobilization of acute lymphoblastic leukemia cells and increases the proportion of cycling cells in the blood in mice. Exp Hematol. 2012; 41(3):293-302.e1. DOI: 10.1016/j.exphem.2012.11.004. View

Corrales L, Glickman L, McWhirter S, Kanne D, Sivick K, Katibah G . Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep. 2015; 11(7):1018-30. PMC: 4440852. DOI: 10.1016/j.celrep.2015.04.031. View

Schimanski C, Bahre R, Gockel I, Muller A, Frerichs K, Horner V . Dissemination of hepatocellular carcinoma is mediated via chemokine receptor CXCR4. Br J Cancer. 2006; 95(2):210-7. PMC: 2360625. DOI: 10.1038/sj.bjc.6603251. View

10.

Duda D, Kozin S, Kirkpatrick N, Xu L, Fukumura D, Jain R . CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies?. Clin Cancer Res. 2011; 17(8):2074-80. PMC: 3079023. DOI: 10.1158/1078-0432.CCR-10-2636. View

11.

Cools-Lartigue J, Spicer J, Najmeh S, Ferri L . Neutrophil extracellular traps in cancer progression. Cell Mol Life Sci. 2014; 71(21):4179-94. PMC: 7096049. DOI: 10.1007/s00018-014-1683-3. View

12.

Begley L, Monteleon C, Shah R, MacDonald J, Macoska J . CXCL12 overexpression and secretion by aging fibroblasts enhance human prostate epithelial proliferation in vitro. Aging Cell. 2005; 4(6):291-8. DOI: 10.1111/j.1474-9726.2005.00173.x. View

13.

Sato A, Klaunberg B, Tolwani R . In vivo bioluminescence imaging. Comp Med. 2005; 54(6):631-4. View

14.

Boimel P, Smirnova T, Ni Zhou Z, Wyckoff J, Park H, Coniglio S . Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res. 2012; 14(1):R23. PMC: 3496141. DOI: 10.1186/bcr3108. View

15.

Sasaki K, Natsugoe S, Ishigami S, Matsumoto M, Okumura H, Setoyama T . Expression of CXCL12 and its receptor CXCR4 in esophageal squamous cell carcinoma. Oncol Rep. 2008; 21(1):65-71. View

16.

Joffre O, Segura E, Savina A, Amigorena S . Cross-presentation by dendritic cells. Nat Rev Immunol. 2012; 12(8):557-69. DOI: 10.1038/nri3254. View

17.

Diamond M, Kinder M, Matsushita H, Mashayekhi M, Dunn G, Archambault J . Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med. 2011; 208(10):1989-2003. PMC: 3182061. DOI: 10.1084/jem.20101158. View

18.

Minamiya Y, Saito H, Takahashi N, Ito M, Imai K, Ono T . Expression of the chemokine receptor CXCR4 correlates with a favorable prognosis in patients with adenocarcinoma of the lung. Lung Cancer. 2009; 68(3):466-71. DOI: 10.1016/j.lungcan.2009.07.015. View

19.

Shaw R, Cantley L . Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006; 441(7092):424-30. DOI: 10.1038/nature04869. View

20.

Smith M, Luker K, Garbow J, Prior J, Jackson E, Piwnica-Worms D . CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res. 2004; 64(23):8604-12. DOI: 10.1158/0008-5472.CAN-04-1844. View