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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
Maeda S, Kamata H, Luo JL, Leffert H, Karin M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell. 2005;121:977–90.
Hou J, Zhou Y, Zheng Y, Fan J, Zhou W, Ng IO, et al. Hepatic RIG-I predicts survival and interferon-alpha therapeutic response in hepatocellular carcinoma. Cancer Cell. 2014;25:49–63.
Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer. 2016;16:131–44.
Paludan SR. Activation and regulation of DNA-driven immune responses. Microbiol Mol Biol Rev. 2015;79:225–41.
Cheon H, Borden EC, Stark GR. Interferons and their stimulated genes in the tumor microenvironment. Semin Oncol. 2014;41:156–73.
Rasmussen SB, Horan KA, Holm CK, Stranks AJ, Mettenleiter TC, Simon AK, et al. Activation of autophagy by alpha-herpesviruses in myeloid cells is mediated by cytoplasmic viral DNA through a mechanism dependent on stimulator of IFN genes. J Immunol. 2011;187:5268–76.
Paludan SR, Reinert LS, Hornung V. DNA-stimulated cell death: implications for host defence, inflammatory diseases and cancer. Nat Rev Immunol. 2019;19:141–53.
Thomsen MK, Nandakumar R, Stadler D, Malo A, Valls RM, Wang F, et al. Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection. Hepatology. 2016;64:746–59.
Zhang CX, Ye SB, Ni JJ, Cai TT, Liu YN, Huang DJ, et al. STING signaling remodels the tumor microenvironment by antagonizing myeloid-derived suppressor cell expansion. Cell Death Differ. 2019;26:2314–28.
Lau L, Gray EE, Brunette RL, Stetson DB. DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway. Science. 2015;350:568–71.
Sokolowska O, Nowis D. STING signaling in cancer cells: important or not? Arch Immunol Ther Exp. 2018;66:125–32.
Ohkuri T, Ghosh A, Kosaka A, Zhu J, Ikeura M, David M, et al. STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer. Immunol Res. 2014;2:1199–208.
Ahn J, Konno H, Barber GN. Diverse roles of STING-dependent signaling on the development of cancer. Oncogene. 2015;34:5302–8.
Zhu Q, Man SM, Gurung P, Liu Z, Vogel P, Lamkanfi M, et al. Cutting edge: STING mediates protection against colorectal tumorigenesis by governing the magnitude of intestinal inflammation. J Immunol. 2014;193:4779–82.
Ahn J, Xia T, Konno H, Konno K, Ruiz P, Barber GN. Inflammation-driven carcinogenesis is mediated through STING. Nat Commun. 2014;5:5166.
Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 2015;11:1018–30.
Li T, Chen ZJ. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med. 2018;215:1287–99.
Iurescia S, Fioretti D, Rinaldi M. Targeting cytosolic nucleic acid-sensing pathways for cancer immunotherapies. Front Immunol. 2018;9:711.
Larkin B, Ilyukha V, Sorokin M, Buzdin A, Vannier E, Poltorak A. Cutting edge: activation of STING in T cells induces type I IFN responses and cell death. J Immunol. 2017;199:397–402.
Gulen MF, Koch U, Haag SM, Schuler F, Apetoh L, Villunger A, et al. Signalling strength determines proapoptotic functions of STING. Nat Commun. 2017;8:427.
Prabakaran T, Bodda C, Krapp C, Zhang BC, Christensen MH, Sun C, et al. Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. EMBO J. 2018;37:1–17.
Zhong Z, Sanchez-Lopez E, Karin M. Autophagy, inflammation, and immunity: a troika governing cancer and its treatment. Cell. 2016;166:288–98.
Skouboe MK, Knudsen A, Reinert LS, Boularan C, Lioux T, Perouzel E, et al. STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice. PLoS Pathog. 2018;14:e1006976.
van Rooijen N, Sanders A, van den Berg TK. Apoptosis of macrophages induced by liposome-mediated intracellular delivery of clodronate and propamidine. J Immunol Methods. 1996;193:93–9.
Sze A, Belgnaoui SM, Olagnier D, Lin R, Hiscott J, van Grevenynghe J. Host restriction factor SAMHD1 limits human T cell leukemia virus type 1 infection of monocytes via STING-mediated apoptosis. Cell Host Microbe. 2013;14:422–34.
Schlageter M, Terracciano LM, D’Angelo S, Sorrentino P. Histopathology of hepatocellular carcinoma. World J Gastroenterol. 2014;20:15955–64.
Muhlbauer M, Fleck M, Schutz C, Weiss T, Froh M, Blank C, et al. PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis. J Hepatol. 2006;45:520–8.
Lucas ED, Finlon JM, Burchill MA, McCarthy MK, Morrison TE, Colpitts TM, et al. Type 1 IFN and PD-L1 coordinate lymphatic endothelial cell expansion and contraction during an inflammatory immune response. J Immunol. 2018;45:520–28.
Haanen JB, Robert C. Immune checkpoint inhibitors. Prog Tumor Res. 2015;42:55–66.
Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–9.
Schoggins JW, MacDuff DA, Imanaka N, Gainey MD, Shrestha B, Eitson JL, et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature. 2014;505:691–5.
Diner EJ, Burdette DL, Wilson SC, Monroe KM, Kellenberger CA, Hyodo M, et al. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep. 2013;3:1355–61.
Jessy T. Immunity over inability: the spontaneous regression of cancer. J Nat Sci Biol Med. 2011;2:43–9.
Sakamaki A, Kamimura K, Abe S, Tsuchiya A, Takamura M, Kawai H, et al. Spontaneous regression of hepatocellular carcinoma: a mini-review. World J Gastroenterol. 2017;23:3797–804.
Ariff B, Lloyd CR, Khan S, Shariff M, Thillainayagam AV, Bansi DS, et al. Imaging of liver cancer. World J Gastroenterol. 2009;15:1289–300.
Takahashi A, Loo TM, Okada R, Kamachi F, Watanabe Y, Wakita M, et al. Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells. Nat Commun. 2018;9:1249.
Yu Y, Liu Y, An W, Song J, Zhang Y, Zhao X. STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis. J Clin Investig. 2019;129:546–55.
Corrales L, Gajewski TF. Molecular pathways: targeting the stimulator of interferon genes (STING) in the immunotherapy of cancer. Clin Cancer Res. 2015;21:4774–9.
Chen D, Tong J, Yang L, Wei L, Stolz DB, Yu J, et al. PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors. Proc Natl Acad Sci USA. 2018;115:3930–5.
Li K, Qu S, Chen X, Wu Q, Shi M. Promising targets for cancer immunotherapy: TLRs, RLRs, and STING-mediated innate immune pathways. Int J Mol Sci. 2017;18:1–19.
Gao P, Zillinger T, Wang W, Ascano M, Dai P, Hartmann G, et al. Binding-pocket and lid-region substitutions render human STING sensitive to the species-specific drug DMXAA. Cell Rep. 2014;8:1668–76.
Young A, Quandt Z, Bluestone JA. The balancing act between cancer immunity and autoimmunity in response to immunotherapy. Cancer Immunol Res. 2018;6:1445–52.
Bakiri L, Wagner EF. Mouse models for liver cancer. Mol Oncol. 2013;7:206–23.
Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375:819–29.
Yeung JT, Hamilton RL, Ohnishi K, Ikeura M, Potter DM, Nikiforova MN, et al. LOH in the HLA class I region at 6p21 is associated with shorter survival in newly diagnosed adult glioblastoma. Clin Cancer Res. 2013;19:1816–26.
Wang H, Hu S, Chen X, Shi H, Chen C, Sun L, et al. cGAS is essential for the antitumor effect of immune checkpoint blockade. Proc Natl Acad Sci USA. 2017;114:1637–42.
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).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
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.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-019-1108-8
This article is cited by
-
The dual function of cGAS-STING signaling axis in liver diseases
Acta Pharmacologica Sinica (2024)
-
Harnessing innate immune pathways for therapeutic advancement in cancer
Signal Transduction and Targeted Therapy (2024)
-
cGAS suppresses hepatocellular carcinoma independent of its cGAMP synthase activity
Cell Death & Differentiation (2024)
-
Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation
Nature Communications (2023)
-
Beyond DNA sensing: expanding the role of cGAS/STING in immunity and diseases
Archives of Pharmacal Research (2023)