GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma
Background A better understanding of the molecular mechanisms that manifest in the immunosuppressive tumor microenvironment (TME) is crucial for developing more efficacious immunotherapies for hepatocellular carcinoma (HCC), which has a poor response to current immunotherapies. Regulatory T (Treg) c...
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| Language: | English |
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BMJ Publishing Group
2021-09-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/9/e002787.full |
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| author | Meng Li Yuan Gao Wei Zhang Zhijun Tan Kuo Zhang Zhaowei Wang Lei He Weina Li Chuanyang Xu Jieyu Zhang Desheng Wang Kefeng Dou Ran Zhuang Boquan Jin Qiang Hao Wangqian Zhang Shuning Wang Jintao Gu Lei Shang Haichuan Su Yingqi Zhang Cun Zhang |
| author_facet | Meng Li Yuan Gao Wei Zhang Zhijun Tan Kuo Zhang Zhaowei Wang Lei He Weina Li Chuanyang Xu Jieyu Zhang Desheng Wang Kefeng Dou Ran Zhuang Boquan Jin Qiang Hao Wangqian Zhang Shuning Wang Jintao Gu Lei Shang Haichuan Su Yingqi Zhang Cun Zhang |
| author_sort | Meng Li |
| collection | DOAJ |
| description | Background A better understanding of the molecular mechanisms that manifest in the immunosuppressive tumor microenvironment (TME) is crucial for developing more efficacious immunotherapies for hepatocellular carcinoma (HCC), which has a poor response to current immunotherapies. Regulatory T (Treg) cells are key mediators of HCC-associated immunosuppression. We investigated the selective mechanism exploited by HCC that lead to Treg cells expansion and to find more efficacious immunotherapies.Methods We used matched tumor tissues and blood samples from 150 patients with HCC to identify key factors of Treg cells expansion. We used mass cytometry (CyTOF) and orthotopic cancer mouse models to analyze overall immunological changes after growth differentiation factor 15 (GDF15) gene ablation in HCC. We used flow cytometry, coimmunoprecipitation, RNA sequencing, mass spectrum, chromatin immunoprecipitation and Gdf15–/–, OT-I and GFP transgenic mice to demonstrate the effects of GDF15 on Treg cells and related molecular mechanism. We used hybridoma technology to generate monoclonal antibody to block GDF15 and evaluate its effects on HCC-associated immunosuppression.Results GDF15 is positively associated with the elevation of Treg cell frequencies in patients wih HCC. Gene ablation of GDF15 in HCC can convert an immunosuppressive TME to an inflammatory state. GDF15 promotes the generation of peripherally derived inducible Treg (iTreg) cells and enhances the suppressive function of natural Treg (nTreg) cells by interacting with a previously unrecognized receptor CD48 on T cells and thus downregulates STUB1, an E3 ligase that mediates forkhead box P3 (FOXP3) protein degradation. GDF15 neutralizing antibody effectively eradicates HCC and augments the antitumor immunity in mouse.Conclusions Our results reveal the generation and function enhancement of Treg cells induced by GDF15 is a new mechanism for HCC-related immunosuppression. CD48 is the first discovered receptor of GDF15 in the immune system which provide the possibility to solve the molecular mechanism of the immunomodulatory function of GDF15. The therapeutic GDF15 blockade achieves HCC clearance without obvious adverse events. |
| format | Article |
| id | doaj-art-d1b9165920ba4fccb35243b894017e8f |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-09-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-d1b9165920ba4fccb35243b894017e8f2025-02-10T06:00:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-09-019910.1136/jitc-2021-002787GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinomaMeng Li0Yuan Gao1Wei Zhang2Zhijun Tan3Kuo Zhang4Zhaowei Wang5Lei He6Weina Li7Chuanyang Xu8Jieyu Zhang9Desheng Wang10Kefeng Dou11Ran Zhuang12Boquan Jin13Qiang Hao14Wangqian Zhang15Shuning Wang16Jintao Gu17Lei Shang18Haichuan Su19Yingqi Zhang20Cun Zhang21Center for the Evaluation of Value and Risk in Health, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, USA6 Neurology, Zhengzhou University First Affiliated Hospital, Zhengzhou, Henan, ChinaState Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaDepartment of Health Statistics, Fourth Military Medical University, Xi’an, Shaanxi, ChinaState Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaDepartment of Neurology, Qianjiang Central Hospital, Qianjiang, Hubei, ChinaThird Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, ChinaState Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaState Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaState Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaDepartment of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, ChinaDepartment of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, ChinaDepartment of Immunology, Fourth Military Medical University, Xi’an, Shaanxi, ChinaDepartment of Immunology, Fourth Military Medical University, Xi’an, Shaanxi, ChinaDepartment of Neurosurgery, Beijing Tiantan Hospital, Beijing, ChinaState Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaState Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaState Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaDepartment of Health Statistics, Fourth Military Medical University, Xi’an, Shaanxi, ChinaDepartment of Oncology, Tangdu Hospital, Air Force Medical University, Xi`an, Shaanxi, ChinaState Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaState Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaBackground A better understanding of the molecular mechanisms that manifest in the immunosuppressive tumor microenvironment (TME) is crucial for developing more efficacious immunotherapies for hepatocellular carcinoma (HCC), which has a poor response to current immunotherapies. Regulatory T (Treg) cells are key mediators of HCC-associated immunosuppression. We investigated the selective mechanism exploited by HCC that lead to Treg cells expansion and to find more efficacious immunotherapies.Methods We used matched tumor tissues and blood samples from 150 patients with HCC to identify key factors of Treg cells expansion. We used mass cytometry (CyTOF) and orthotopic cancer mouse models to analyze overall immunological changes after growth differentiation factor 15 (GDF15) gene ablation in HCC. We used flow cytometry, coimmunoprecipitation, RNA sequencing, mass spectrum, chromatin immunoprecipitation and Gdf15–/–, OT-I and GFP transgenic mice to demonstrate the effects of GDF15 on Treg cells and related molecular mechanism. We used hybridoma technology to generate monoclonal antibody to block GDF15 and evaluate its effects on HCC-associated immunosuppression.Results GDF15 is positively associated with the elevation of Treg cell frequencies in patients wih HCC. Gene ablation of GDF15 in HCC can convert an immunosuppressive TME to an inflammatory state. GDF15 promotes the generation of peripherally derived inducible Treg (iTreg) cells and enhances the suppressive function of natural Treg (nTreg) cells by interacting with a previously unrecognized receptor CD48 on T cells and thus downregulates STUB1, an E3 ligase that mediates forkhead box P3 (FOXP3) protein degradation. GDF15 neutralizing antibody effectively eradicates HCC and augments the antitumor immunity in mouse.Conclusions Our results reveal the generation and function enhancement of Treg cells induced by GDF15 is a new mechanism for HCC-related immunosuppression. CD48 is the first discovered receptor of GDF15 in the immune system which provide the possibility to solve the molecular mechanism of the immunomodulatory function of GDF15. The therapeutic GDF15 blockade achieves HCC clearance without obvious adverse events.https://jitc.bmj.com/content/9/9/e002787.full |
| spellingShingle | Meng Li Yuan Gao Wei Zhang Zhijun Tan Kuo Zhang Zhaowei Wang Lei He Weina Li Chuanyang Xu Jieyu Zhang Desheng Wang Kefeng Dou Ran Zhuang Boquan Jin Qiang Hao Wangqian Zhang Shuning Wang Jintao Gu Lei Shang Haichuan Su Yingqi Zhang Cun Zhang GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma Journal for ImmunoTherapy of Cancer |
| title | GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma |
| title_full | GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma |
| title_fullStr | GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma |
| title_full_unstemmed | GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma |
| title_short | GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma |
| title_sort | gdf15 induces immunosuppression via cd48 on regulatory t cells in hepatocellular carcinoma |
| url | https://jitc.bmj.com/content/9/9/e002787.full |
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