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The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and the incidence of HCC is increasing. Recently, cancer immunotherapy has emerged as an efficient treatment against some cancers. Here we have used a mouse model of mutagen-induced HCC to explore the therapeutic usefulness of targeting the DNA-activated STING pathway in HCC. STING-deficient mice exhibited unaltered initial development of HCC, but had higher number of large tumors at late stages of disease. In the liver of STING-deficient HCC mice, we observed reduced levels of phospho-STAT1, autophagy, and cleaved caspase3. These responses were activated in the liver by treatment with a cyclic dinucleotide (CDN) STING agonist. Importantly, CDN treatment of mice after HCC development efficiently reduced tumor size. Initiation of CDN treatment at an even later stage of disease to allow HCC detection by MR scanning revealed that the majority of tumors regressed in response to CDN, but new tumors were also detected, which were unresponsive to CDN treatment. Overall, the modulation of the STING pathway affects the development of HCC, and holds promise for a use as a treatment of this disease, most likely in combination with other immunomodulatory treatments such as PD1 inhibitors or with standard of care.

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Acknowledgements

We thank Mette Simonsen for assistant with scanning, Latifa Bakiri for thoroughly reading and comments on the manuscript, and Kirsten S Petersen for technical assistance. This work was funded by the Danish Medical Research Council (grants nos: 12–124330 and DFF–6110–00068), the Lundbeck Foundation (grant no R198–2015–171), and an unrestricted research grant from InvivoGen (all to SRP). MKT was funded by a fellowship sponsored by InvivoGen, Danish Cancer Society (R146-A9394-16-S2 and R204-A12490), Ministry of health (4–1612–236/7), and AUFF NOVA (E-2o15-FLS-9-8).

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Correspondence to Martin K. Thomsen or Søren R. Paludan.

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CB, FV, TL, EP, and MT are employees of InvivoGen. InvivoGen have partly funded this work, and the company has financial interests in STING agonists, including some used in this study. However, the grant from InvivoGen was unrestricted, and the funding source had no impact on the development of the project.

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Thomsen, M.K., Skouboe, M.K., Boularan, C. et al. The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma. Oncogene 39, 1652–1664 (2020). https://doi.org/10.1038/s41388-019-1108-8

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