HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells
Abstract Myeloid-derived suppressor cells (MDSCs) play a critical role in cancer progression and resistance, thus representing promising targets for immunotherapy. Despite the established role of histone deacetylases (HDACs) in epigenetic regulation of cell fate and function, their specific impact o...
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| Format: | Article |
| Language: | English |
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Springer
2025-02-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-024-03931-y |
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| author | Zhiqi Xie Jinjin Shao Zeren Shen Zhichao Ye Yoshiaki Okada Daisuke Okuzaki Naoki Okada Masashi Tachibana |
| author_facet | Zhiqi Xie Jinjin Shao Zeren Shen Zhichao Ye Yoshiaki Okada Daisuke Okuzaki Naoki Okada Masashi Tachibana |
| author_sort | Zhiqi Xie |
| collection | DOAJ |
| description | Abstract Myeloid-derived suppressor cells (MDSCs) play a critical role in cancer progression and resistance, thus representing promising targets for immunotherapy. Despite the established role of histone deacetylases (HDACs) in epigenetic regulation of cell fate and function, their specific impact on MDSCs remains elusive. We sought to investigate the effects and underlying mechanisms of HDAC on MDSCs using various HDAC inhibitors. Our results indicate that HDAC1-3 inhibitors reduce CCR2 expression, a chemokine receptor that mediates the migration of monocytic (M-)MDSCs to tumors and attenuated the immunosuppressive activity of MDSCs. In an orthotropic hepatocellular carcinoma (HCC) murine model, HDAC1-3 inhibitors reduced the infiltration of M-MDSCs, increased the number of natural killer cells in tumors, and suppressed tumor growth. Our results also suggest that HDAC1-3 inhibitors potentiate the antitumor effects of anti-programmed cell death protein 1 antibodies. ATAC-seq and RNA-seq analyses revealed 115 genes epigenetically upregulated by HDAC1-3 inhibitors, primarily linked to transcriptional regulation and ubiquitination. We further elucidated that HDAC1-3 inhibitors facilitate CCR2 protein degradation through ubiquitination-mediated by NEDD4 E3 ligase. Our findings reveal a novel mechanism of action of HDAC1-3 inhibitors in MDSCs and suggest a potential synergistic immunotherapy strategy for clinical benefit in HCC. |
| format | Article |
| id | doaj-art-8563f410ea1342b38275d5a22b11cc63 |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-8563f410ea1342b38275d5a22b11cc632025-02-02T12:26:17ZengSpringerCancer Immunology, Immunotherapy1432-08512025-02-0174311310.1007/s00262-024-03931-yHDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cellsZhiqi Xie0Jinjin Shao1Zeren Shen2Zhichao Ye3Yoshiaki Okada4Daisuke Okuzaki5Naoki Okada6Masashi Tachibana7Wuyi First People’s Hospital, Affiliated Hospital, School of Medicine, Hangzhou City UniversityKey Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical CollegeDepartment of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityKey Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical CollegeLaboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka UniversityLaboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, Osaka UniversityProject for Vaccine and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka UniversityProject for Vaccine and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka UniversityAbstract Myeloid-derived suppressor cells (MDSCs) play a critical role in cancer progression and resistance, thus representing promising targets for immunotherapy. Despite the established role of histone deacetylases (HDACs) in epigenetic regulation of cell fate and function, their specific impact on MDSCs remains elusive. We sought to investigate the effects and underlying mechanisms of HDAC on MDSCs using various HDAC inhibitors. Our results indicate that HDAC1-3 inhibitors reduce CCR2 expression, a chemokine receptor that mediates the migration of monocytic (M-)MDSCs to tumors and attenuated the immunosuppressive activity of MDSCs. In an orthotropic hepatocellular carcinoma (HCC) murine model, HDAC1-3 inhibitors reduced the infiltration of M-MDSCs, increased the number of natural killer cells in tumors, and suppressed tumor growth. Our results also suggest that HDAC1-3 inhibitors potentiate the antitumor effects of anti-programmed cell death protein 1 antibodies. ATAC-seq and RNA-seq analyses revealed 115 genes epigenetically upregulated by HDAC1-3 inhibitors, primarily linked to transcriptional regulation and ubiquitination. We further elucidated that HDAC1-3 inhibitors facilitate CCR2 protein degradation through ubiquitination-mediated by NEDD4 E3 ligase. Our findings reveal a novel mechanism of action of HDAC1-3 inhibitors in MDSCs and suggest a potential synergistic immunotherapy strategy for clinical benefit in HCC.https://doi.org/10.1007/s00262-024-03931-yMyeloid-derived suppressor cellsHistone deacetylaseNEDD4CCR2Hepatocellular carcinoma |
| spellingShingle | Zhiqi Xie Jinjin Shao Zeren Shen Zhichao Ye Yoshiaki Okada Daisuke Okuzaki Naoki Okada Masashi Tachibana HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells Cancer Immunology, Immunotherapy Myeloid-derived suppressor cells Histone deacetylase NEDD4 CCR2 Hepatocellular carcinoma |
| title | HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells |
| title_full | HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells |
| title_fullStr | HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells |
| title_full_unstemmed | HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells |
| title_short | HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells |
| title_sort | hdac1 3 inhibition triggers nedd4 mediated ccr2 downregulation and attenuates immunosuppression in myeloid derived suppressor cells |
| topic | Myeloid-derived suppressor cells Histone deacetylase NEDD4 CCR2 Hepatocellular carcinoma |
| url | https://doi.org/10.1007/s00262-024-03931-y |
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