System analysis based on the cancer–immunity cycle identifies ZNF207 as a novel immunotherapy target for hepatocellular carcinoma
Background Immune checkpoint inhibitors as monotherapies for advanced hepatocellular carcinoma (HCC) fail to achieve satisfying results, while combination therapies show greater efficacy. Therefore, identifying new combined targets for immune checkpoint inhibitors could be promising.Methods We combi...
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| Language: | English |
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004414.full |
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| author | Yu Wang Yong Yang Xu Wang Xinying Tang Tao Zhou Haoyu Wang Xingyi Chen Yushi Ding Haoyang Tu Shengyang Gao |
| author_facet | Yu Wang Yong Yang Xu Wang Xinying Tang Tao Zhou Haoyu Wang Xingyi Chen Yushi Ding Haoyang Tu Shengyang Gao |
| author_sort | Yu Wang |
| collection | DOAJ |
| description | Background Immune checkpoint inhibitors as monotherapies for advanced hepatocellular carcinoma (HCC) fail to achieve satisfying results, while combination therapies show greater efficacy. Therefore, identifying new combined targets for immune checkpoint inhibitors could be promising.Methods We combined the cancer–immunity cycle score with weighted gene coexpression network and system analyses to screen immunosuppressive targets in HCC. In vitro and in vivo experiments were used to assess the effect of zinc finger protein 207 (ZNF207) on HCC immunity. RNA sequencing, metabolomic, cytokine array analysis, dual-luciferase reporter gene assay, and ChIP quantitative PCR assay were used to investigate the role of ZNF207 in tumor immunity regulation.Results The system analysis and experimental verification revealed ZNF207 as an immunosuppressive target in HCC. Hypoxia-induced upregulation of ZNF207 promoted HCC progression in immunocompetent mice while being associated with decreased CD8+ T-cell infiltration and increased exhaustion. Mechanistically, the mitogen-activated protein kinase (MAPK)–chemokine C-X3-C-motif ligand axis was involved in ZNF207-mediated CD8+ T-cell chemotaxis. Furthermore, ZNF207 transcriptionally regulated indoleamine 2,3-dioxygenase 1 and elevated kynurenine levels, leading to the exhaustion of CD8+ T cells. Patients with lower ZNF207 expression were more sensitive to antiprogrammed cell death protein 1 (PD1) therapy, and silencing ZNF207 could be beneficial to anti-PD1 combination therapy.Conclusion Our study implicates ZNF207 in suppressing the HCC microenvironment and showed the feasibility of targeting ZNF207 during anti-PD1 therapy in HCC. |
| format | Article |
| id | doaj-art-ed11e0a5235f47d882564bfb6e7cd2ea |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ed11e0a5235f47d882564bfb6e7cd2ea2025-08-20T02:11:35ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-004414System analysis based on the cancer–immunity cycle identifies ZNF207 as a novel immunotherapy target for hepatocellular carcinomaYu Wang0Yong Yang1Xu Wang2Xinying Tang3Tao Zhou4Haoyu Wang5Xingyi Chen6Yushi Ding7Haoyang Tu8Shengyang Gao9Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaThe First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, ChinaDepartment of Thoracic Surgery, Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, Hubei, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, ChinaSchool of Public Health, Nanjing Medical University, Nanjing, Jiangsu, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China5 Department of Medical, Tongji University Affilliated East Hospital, Shanghai, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, ChinaBackground Immune checkpoint inhibitors as monotherapies for advanced hepatocellular carcinoma (HCC) fail to achieve satisfying results, while combination therapies show greater efficacy. Therefore, identifying new combined targets for immune checkpoint inhibitors could be promising.Methods We combined the cancer–immunity cycle score with weighted gene coexpression network and system analyses to screen immunosuppressive targets in HCC. In vitro and in vivo experiments were used to assess the effect of zinc finger protein 207 (ZNF207) on HCC immunity. RNA sequencing, metabolomic, cytokine array analysis, dual-luciferase reporter gene assay, and ChIP quantitative PCR assay were used to investigate the role of ZNF207 in tumor immunity regulation.Results The system analysis and experimental verification revealed ZNF207 as an immunosuppressive target in HCC. Hypoxia-induced upregulation of ZNF207 promoted HCC progression in immunocompetent mice while being associated with decreased CD8+ T-cell infiltration and increased exhaustion. Mechanistically, the mitogen-activated protein kinase (MAPK)–chemokine C-X3-C-motif ligand axis was involved in ZNF207-mediated CD8+ T-cell chemotaxis. Furthermore, ZNF207 transcriptionally regulated indoleamine 2,3-dioxygenase 1 and elevated kynurenine levels, leading to the exhaustion of CD8+ T cells. Patients with lower ZNF207 expression were more sensitive to antiprogrammed cell death protein 1 (PD1) therapy, and silencing ZNF207 could be beneficial to anti-PD1 combination therapy.Conclusion Our study implicates ZNF207 in suppressing the HCC microenvironment and showed the feasibility of targeting ZNF207 during anti-PD1 therapy in HCC.https://jitc.bmj.com/content/10/3/e004414.full |
| spellingShingle | Yu Wang Yong Yang Xu Wang Xinying Tang Tao Zhou Haoyu Wang Xingyi Chen Yushi Ding Haoyang Tu Shengyang Gao System analysis based on the cancer–immunity cycle identifies ZNF207 as a novel immunotherapy target for hepatocellular carcinoma Journal for ImmunoTherapy of Cancer |
| title | System analysis based on the cancer–immunity cycle identifies ZNF207 as a novel immunotherapy target for hepatocellular carcinoma |
| title_full | System analysis based on the cancer–immunity cycle identifies ZNF207 as a novel immunotherapy target for hepatocellular carcinoma |
| title_fullStr | System analysis based on the cancer–immunity cycle identifies ZNF207 as a novel immunotherapy target for hepatocellular carcinoma |
| title_full_unstemmed | System analysis based on the cancer–immunity cycle identifies ZNF207 as a novel immunotherapy target for hepatocellular carcinoma |
| title_short | System analysis based on the cancer–immunity cycle identifies ZNF207 as a novel immunotherapy target for hepatocellular carcinoma |
| title_sort | system analysis based on the cancer immunity cycle identifies znf207 as a novel immunotherapy target for hepatocellular carcinoma |
| url | https://jitc.bmj.com/content/10/3/e004414.full |
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