Memory-promoting function of miR-379-5p attenuates CD8+ T cell exhaustion by targeting immune checkpoints
Background MicroRNAs (miRNAs) are epigenetic regulators of T cell maturation and exhaustion. However, the mechanisms by which miRNAs influence T cell function in tumor environments remain unclear. This study focuses on miR-379-5p, which counteracts T cell exhaustion and enhances antitumor responses....
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BMJ Publishing Group
2025-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/4/e010363.full |
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| author | Chia-Hsin Liu Hong-Wei Li Liang-Chih Liu You-Zhe Lin Wan-Rong Wu Ting-Yi Liao Chuan-Chun Lee Feng-Chi Chung Yi-Chun Shen Guan-Yu Zhuo Wei-Chung Cheng Shao-Chun Wang |
| author_facet | Chia-Hsin Liu Hong-Wei Li Liang-Chih Liu You-Zhe Lin Wan-Rong Wu Ting-Yi Liao Chuan-Chun Lee Feng-Chi Chung Yi-Chun Shen Guan-Yu Zhuo Wei-Chung Cheng Shao-Chun Wang |
| author_sort | Chia-Hsin Liu |
| collection | DOAJ |
| description | Background MicroRNAs (miRNAs) are epigenetic regulators of T cell maturation and exhaustion. However, the mechanisms by which miRNAs influence T cell function in tumor environments remain unclear. This study focuses on miR-379-5p, which counteracts T cell exhaustion and enhances antitumor responses.Methods Native CD8+ T cells were isolated from the blood of healthy donors and subjected to chronic stimulation to induce exhaustion. RNA sequencing and miRNA sequencing were performed to identify differentially expressed miRNAs. These miRNAs underwent bioinformatics analyses, including DESeq enrichment, immune cell infiltration assessment, and patient prognostic outcomes in The Cancer Genome Atlas data sets to assess their potential involvement in T cell exhaustion and antitumor immunity. The biological functions of miRNA on T cell differentiation, cytotoxic killing, and immune checkpoint regulation were investigated using in vitro assays, OT-I B16F10-OVA models, and patient-derived tumor organoids.Results MiR-379-5p is downregulated in exhausted T cells and negatively associated with exhausted tumor-infiltrating lymphocytes in advanced tumors. It correlates positively with better survival outcomes in breast cancer, cervical cancer and melanoma. In CD8+ T cells, miR-379-5p reduces the expression of immune checkpoint proteins T cell immunoglobulin and mucin-domain containing-3 (TIM3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) by targeting their 3’ untranslated region. Overexpression of miR-379-5p in CD8+ T cell promotes differentiation into memory-like T effector cells and enhances cytotoxic killing of cancer cells. The transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) with increased expression in exhausted T cells and negatively regulates miR-379, restoring immune checkpoint expression and suppressing cancer-killing ability. In contrast, OT-I T cells expressing ectopic miR-379-5p show increased cytotoxicity against B16F10-OVA tumors in mice. Autologous T cells isolated from patients with breast cancer transduced with miR-379-5p significantly improve killing of tumor organoids derived from the same patients.Conclusions MiR-379-5p acts as an epigenetic tumor suppressor by enhancing CD8+ T cell effector functions and suppressing T cell exhaustion. MiR-379-5p could represent a novel marker and strategy for cancer immunotherapy, offering promising avenues for enhancing antitumor immune responses. |
| format | Article |
| id | doaj-art-d72b6a0432cd45fdb74acb75d3c3d545 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-d72b6a0432cd45fdb74acb75d3c3d5452025-08-20T03:03:38ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-04-0113410.1136/jitc-2024-010363Memory-promoting function of miR-379-5p attenuates CD8+ T cell exhaustion by targeting immune checkpointsChia-Hsin Liu0Hong-Wei Li1Liang-Chih Liu2You-Zhe Lin3Wan-Rong Wu4Ting-Yi Liao5Chuan-Chun Lee6Feng-Chi Chung7Yi-Chun Shen8Guan-Yu Zhuo9Wei-Chung Cheng10Shao-Chun Wang11Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, TaiwanCancer Biology and Precision Therapeutics Center, China Medical University, Taichung, TaiwanDepartment of Surgery, China Medical University Hospital, Taichung, TaiwanCancer Biology and Precision Therapeutics Center, China Medical University, Taichung, TaiwanGraduate Institute of Biomedical Sciences, China Medical University, Taichung, TaiwanGraduate Institute of Biomedical Sciences, China Medical University, Taichung, TaiwanCenter for Molecular Medicine, China Medical University Hospital, Taichung, TaiwanProgram for Cancer Biology and Drug Discovery, China Medical University, Taichung, TaiwanCenter for Molecular Medicine, China Medical University Hospital, Taichung, TaiwanInstitute of Translational Medicine and New Drug Development, China Medical University, Taichung, TaiwanCancer Biology and Precision Therapeutics Center, China Medical University, Taichung, TaiwanCancer Biology and Precision Therapeutics Center, China Medical University, Taichung, TaiwanBackground MicroRNAs (miRNAs) are epigenetic regulators of T cell maturation and exhaustion. However, the mechanisms by which miRNAs influence T cell function in tumor environments remain unclear. This study focuses on miR-379-5p, which counteracts T cell exhaustion and enhances antitumor responses.Methods Native CD8+ T cells were isolated from the blood of healthy donors and subjected to chronic stimulation to induce exhaustion. RNA sequencing and miRNA sequencing were performed to identify differentially expressed miRNAs. These miRNAs underwent bioinformatics analyses, including DESeq enrichment, immune cell infiltration assessment, and patient prognostic outcomes in The Cancer Genome Atlas data sets to assess their potential involvement in T cell exhaustion and antitumor immunity. The biological functions of miRNA on T cell differentiation, cytotoxic killing, and immune checkpoint regulation were investigated using in vitro assays, OT-I B16F10-OVA models, and patient-derived tumor organoids.Results MiR-379-5p is downregulated in exhausted T cells and negatively associated with exhausted tumor-infiltrating lymphocytes in advanced tumors. It correlates positively with better survival outcomes in breast cancer, cervical cancer and melanoma. In CD8+ T cells, miR-379-5p reduces the expression of immune checkpoint proteins T cell immunoglobulin and mucin-domain containing-3 (TIM3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) by targeting their 3’ untranslated region. Overexpression of miR-379-5p in CD8+ T cell promotes differentiation into memory-like T effector cells and enhances cytotoxic killing of cancer cells. The transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) with increased expression in exhausted T cells and negatively regulates miR-379, restoring immune checkpoint expression and suppressing cancer-killing ability. In contrast, OT-I T cells expressing ectopic miR-379-5p show increased cytotoxicity against B16F10-OVA tumors in mice. Autologous T cells isolated from patients with breast cancer transduced with miR-379-5p significantly improve killing of tumor organoids derived from the same patients.Conclusions MiR-379-5p acts as an epigenetic tumor suppressor by enhancing CD8+ T cell effector functions and suppressing T cell exhaustion. MiR-379-5p could represent a novel marker and strategy for cancer immunotherapy, offering promising avenues for enhancing antitumor immune responses.https://jitc.bmj.com/content/13/4/e010363.full |
| spellingShingle | Chia-Hsin Liu Hong-Wei Li Liang-Chih Liu You-Zhe Lin Wan-Rong Wu Ting-Yi Liao Chuan-Chun Lee Feng-Chi Chung Yi-Chun Shen Guan-Yu Zhuo Wei-Chung Cheng Shao-Chun Wang Memory-promoting function of miR-379-5p attenuates CD8+ T cell exhaustion by targeting immune checkpoints Journal for ImmunoTherapy of Cancer |
| title | Memory-promoting function of miR-379-5p attenuates CD8+ T cell exhaustion by targeting immune checkpoints |
| title_full | Memory-promoting function of miR-379-5p attenuates CD8+ T cell exhaustion by targeting immune checkpoints |
| title_fullStr | Memory-promoting function of miR-379-5p attenuates CD8+ T cell exhaustion by targeting immune checkpoints |
| title_full_unstemmed | Memory-promoting function of miR-379-5p attenuates CD8+ T cell exhaustion by targeting immune checkpoints |
| title_short | Memory-promoting function of miR-379-5p attenuates CD8+ T cell exhaustion by targeting immune checkpoints |
| title_sort | memory promoting function of mir 379 5p attenuates cd8 t cell exhaustion by targeting immune checkpoints |
| url | https://jitc.bmj.com/content/13/4/e010363.full |
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