MiR-125b-5p modulates the function of regulatory T cells in tumor microenvironment by targeting TNFR2
Background Tumor necrosis factor receptor type 2 (TNFR2) is primarily expressed by CD4+FoxP3+ regulatory T cells (Tregs), especially those present in tumor microenvironment. There is compelling evidence that TNFR2 plays a crucial role in the activation, expansion, and phenotypic stability of Tregs a...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/11/e005241.full |
| _version_ | 1811193168084860928 |
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| author | Xin Chen Hui Li Yang Yang Ping Li Ping Liao Yifei Wang Mengmeng Jiang Liling Niu Yibo Chen Jingbin Zheng Fengyang Chen Huanhuan He |
| author_facet | Xin Chen Hui Li Yang Yang Ping Li Ping Liao Yifei Wang Mengmeng Jiang Liling Niu Yibo Chen Jingbin Zheng Fengyang Chen Huanhuan He |
| author_sort | Xin Chen |
| collection | DOAJ |
| description | Background Tumor necrosis factor receptor type 2 (TNFR2) is primarily expressed by CD4+FoxP3+ regulatory T cells (Tregs), especially those present in tumor microenvironment. There is compelling evidence that TNFR2 plays a crucial role in the activation, expansion, and phenotypic stability of Tregs and promotes tumor immune evasion. Understanding of epigenetic regulation of TNFR2 expression in Tregs may help device a novel strategy in cancer immunotherapy.Methods MiR-125b-5p-overexpressing or knockdown murine CD4 T cells and Tregs were constructed, and the effect of miR-125b-5p on Tregs proliferation, suppressive function and TNFR2 expression were examined. In vivo antitumor efficacy of Ago-125b-5p (miR-125b-5p agomir) was evaluated in MC38 tumor bearing mice, and tumor-infiltrating Tregs and CD8+ cytotoxic T lymphocytes (CTLs) were analyzed. RNA-seq analysis was applied to reveal the genes and signaling pathways regulated by miR-125b-5p in Tregs.Results In this study, we found that TNFR2 was a direct target of miR-125b-5p. Overexpression of miR-125b-5p decreased the proportion of Tregs and their expression of TNFR2 and consequently inhibited its proliferation and suppressive function by regulating the metabolism-related signaling pathways. Moreover, in colon cancer bearing mice, the administration of Ago-125b-5p markedly inhibited the tumor growth, which was associated with reduction of Tregs and increase of IFNγ+CD8+ T cells in tumor environment. Furthermore, in human colon adenocarcinoma patients, we verified that miR-125b-5p expression was downregulated, and low levels of miR-125b-5p were associated with poor prognosis. Interestingly, the expression of miR-125b-5p and TNFR2 were negatively correlated.Conclusions Our study for the first time found that the expression of TNFR2 by Tregs was regulated by miR-125b-5p. Our results showed that miR-125b-5p had the capacity to inhibit the expression of TNFR2 and immunosuppressive activity of Tregs and consequently enhanced the antitumor efficacy. This property of miR-125b-5p may be therapeutically harnessed in the treatment of human cancers. |
| first_indexed | 2024-04-12T00:04:05Z |
| format | Article |
| id | doaj.art-7cd12e0a6e33455894ee1799086402ee |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-12T00:04:05Z |
| publishDate | 2022-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-7cd12e0a6e33455894ee1799086402ee2022-12-22T03:56:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-11-01101110.1136/jitc-2022-005241MiR-125b-5p modulates the function of regulatory T cells in tumor microenvironment by targeting TNFR2Xin Chen0Hui Li1Yang Yang2Ping Li3Ping Liao4Yifei Wang5Mengmeng Jiang6Liling Niu7Yibo Chen8Jingbin Zheng9Fengyang Chen10Huanhuan He11State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, ChinaDepartment of Social Medicine and Health Management, School of Public Health, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaDepartment of Radiology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, ChinaDepartment of Head and Neck Oncology, West China School of Medicine, West China Hospital of Sichuan University, Chengdu, China1 Hunan Key Laboratory of Pharmacogenetics, Department of Clinical Pharmacology, Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liao Ning; andInstitute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, ChinaDepartment of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, ChinaInstitute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, ChinaInstitute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, ChinaInstitute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, ChinaGuangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, ChinaBackground Tumor necrosis factor receptor type 2 (TNFR2) is primarily expressed by CD4+FoxP3+ regulatory T cells (Tregs), especially those present in tumor microenvironment. There is compelling evidence that TNFR2 plays a crucial role in the activation, expansion, and phenotypic stability of Tregs and promotes tumor immune evasion. Understanding of epigenetic regulation of TNFR2 expression in Tregs may help device a novel strategy in cancer immunotherapy.Methods MiR-125b-5p-overexpressing or knockdown murine CD4 T cells and Tregs were constructed, and the effect of miR-125b-5p on Tregs proliferation, suppressive function and TNFR2 expression were examined. In vivo antitumor efficacy of Ago-125b-5p (miR-125b-5p agomir) was evaluated in MC38 tumor bearing mice, and tumor-infiltrating Tregs and CD8+ cytotoxic T lymphocytes (CTLs) were analyzed. RNA-seq analysis was applied to reveal the genes and signaling pathways regulated by miR-125b-5p in Tregs.Results In this study, we found that TNFR2 was a direct target of miR-125b-5p. Overexpression of miR-125b-5p decreased the proportion of Tregs and their expression of TNFR2 and consequently inhibited its proliferation and suppressive function by regulating the metabolism-related signaling pathways. Moreover, in colon cancer bearing mice, the administration of Ago-125b-5p markedly inhibited the tumor growth, which was associated with reduction of Tregs and increase of IFNγ+CD8+ T cells in tumor environment. Furthermore, in human colon adenocarcinoma patients, we verified that miR-125b-5p expression was downregulated, and low levels of miR-125b-5p were associated with poor prognosis. Interestingly, the expression of miR-125b-5p and TNFR2 were negatively correlated.Conclusions Our study for the first time found that the expression of TNFR2 by Tregs was regulated by miR-125b-5p. Our results showed that miR-125b-5p had the capacity to inhibit the expression of TNFR2 and immunosuppressive activity of Tregs and consequently enhanced the antitumor efficacy. This property of miR-125b-5p may be therapeutically harnessed in the treatment of human cancers.https://jitc.bmj.com/content/10/11/e005241.full |
| spellingShingle | Xin Chen Hui Li Yang Yang Ping Li Ping Liao Yifei Wang Mengmeng Jiang Liling Niu Yibo Chen Jingbin Zheng Fengyang Chen Huanhuan He MiR-125b-5p modulates the function of regulatory T cells in tumor microenvironment by targeting TNFR2 Journal for ImmunoTherapy of Cancer |
| title | MiR-125b-5p modulates the function of regulatory T cells in tumor microenvironment by targeting TNFR2 |
| title_full | MiR-125b-5p modulates the function of regulatory T cells in tumor microenvironment by targeting TNFR2 |
| title_fullStr | MiR-125b-5p modulates the function of regulatory T cells in tumor microenvironment by targeting TNFR2 |
| title_full_unstemmed | MiR-125b-5p modulates the function of regulatory T cells in tumor microenvironment by targeting TNFR2 |
| title_short | MiR-125b-5p modulates the function of regulatory T cells in tumor microenvironment by targeting TNFR2 |
| title_sort | mir 125b 5p modulates the function of regulatory t cells in tumor microenvironment by targeting tnfr2 |
| url | https://jitc.bmj.com/content/10/11/e005241.full |
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