Epigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression
Abstract Programmed death-ligand 1 (PD-L1) ensures that tumor cells escape T-cell-mediated tumor immune surveillance. However, gliomas are characteristic of the low immune response and high-resistance therapy, it is necessary to understand molecular regulatory mechanisms in glioblastoma, especially...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05878-x |
| _version_ | 1827922798635384832 |
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| author | Shengwen Long Guixiang Huang Mi Ouyang Kai Xiao Hao Zhou Anyi Hou Zhiwei Li Zhe Zhong Dongmei Zhong Qinghao Wang Shuanglin Xiang Xiaofeng Ding |
| author_facet | Shengwen Long Guixiang Huang Mi Ouyang Kai Xiao Hao Zhou Anyi Hou Zhiwei Li Zhe Zhong Dongmei Zhong Qinghao Wang Shuanglin Xiang Xiaofeng Ding |
| author_sort | Shengwen Long |
| collection | DOAJ |
| description | Abstract Programmed death-ligand 1 (PD-L1) ensures that tumor cells escape T-cell-mediated tumor immune surveillance. However, gliomas are characteristic of the low immune response and high-resistance therapy, it is necessary to understand molecular regulatory mechanisms in glioblastoma, especially the limited regulation of PD-L1 expression. Herein, we show that low expression of AP-2α is correlated with high expression of PD-L1 in high-grade glioma tissues. AP-2α binds directly to the promoter of the CD274 gene, not only inhibits the transcriptional activity of PD-L1 but enhances endocytosis and degradation of PD-L1 proteins. Overexpression of AP-2α in gliomas enhances CD8+ T cell-mediated proliferation, effector cytokine secretion, and cytotoxicity in vitro. Tfap2a could increase the cytotoxic effect of Cd8+ T cells in CT26, B16F10, and GL261 tumor-immune models, improve anti-tumor immunity, and promote the efficacy of anti-PD-1 therapy. Finally, the EZH2/H3K27Me3/DNMT1 complex mediates the methylation modification of AP-2α gene and maintains low expression of AP-2α in gliomas. 5-Aza-dC (Decitabine) treatment combines with anti-PD-1 immunotherapy to efficiently suppress the progression of GL261 gliomas. Overall, these data support a mechanism of epigenetic modification of AP-2α that contributes to tumor immune evasion, and reactivation of AP-2α synergizes with anti-PD-1 antibodies to increase antitumor efficacy, which may be a broadly applicable strategy in solid tumors. |
| first_indexed | 2024-03-13T04:47:54Z |
| format | Article |
| id | doaj.art-d56b9e66bdee494e8992c5af6fe4545b |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-13T04:47:54Z |
| publishDate | 2023-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-d56b9e66bdee494e8992c5af6fe4545b2023-06-18T11:26:12ZengNature Publishing GroupCell Death and Disease2041-48892023-06-0114611210.1038/s41419-023-05878-xEpigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expressionShengwen Long0Guixiang Huang1Mi Ouyang2Kai Xiao3Hao Zhou4Anyi Hou5Zhiwei Li6Zhe Zhong7Dongmei Zhong8Qinghao Wang9Shuanglin Xiang10Xiaofeng Ding11The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal UniversityDepartment of Neurosurgery, Xiangya Hospital of Central South UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal UniversityDepartment of Neurosurgery, Hunan Provincial Tumor Hospital, The Affiliated Tumor Hospital of Xiangya Medical School of Central South UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal UniversityAbstract Programmed death-ligand 1 (PD-L1) ensures that tumor cells escape T-cell-mediated tumor immune surveillance. However, gliomas are characteristic of the low immune response and high-resistance therapy, it is necessary to understand molecular regulatory mechanisms in glioblastoma, especially the limited regulation of PD-L1 expression. Herein, we show that low expression of AP-2α is correlated with high expression of PD-L1 in high-grade glioma tissues. AP-2α binds directly to the promoter of the CD274 gene, not only inhibits the transcriptional activity of PD-L1 but enhances endocytosis and degradation of PD-L1 proteins. Overexpression of AP-2α in gliomas enhances CD8+ T cell-mediated proliferation, effector cytokine secretion, and cytotoxicity in vitro. Tfap2a could increase the cytotoxic effect of Cd8+ T cells in CT26, B16F10, and GL261 tumor-immune models, improve anti-tumor immunity, and promote the efficacy of anti-PD-1 therapy. Finally, the EZH2/H3K27Me3/DNMT1 complex mediates the methylation modification of AP-2α gene and maintains low expression of AP-2α in gliomas. 5-Aza-dC (Decitabine) treatment combines with anti-PD-1 immunotherapy to efficiently suppress the progression of GL261 gliomas. Overall, these data support a mechanism of epigenetic modification of AP-2α that contributes to tumor immune evasion, and reactivation of AP-2α synergizes with anti-PD-1 antibodies to increase antitumor efficacy, which may be a broadly applicable strategy in solid tumors.https://doi.org/10.1038/s41419-023-05878-x |
| spellingShingle | Shengwen Long Guixiang Huang Mi Ouyang Kai Xiao Hao Zhou Anyi Hou Zhiwei Li Zhe Zhong Dongmei Zhong Qinghao Wang Shuanglin Xiang Xiaofeng Ding Epigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression Cell Death and Disease |
| title | Epigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression |
| title_full | Epigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression |
| title_fullStr | Epigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression |
| title_full_unstemmed | Epigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression |
| title_short | Epigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression |
| title_sort | epigenetically modified ap 2α by dna methyltransferase facilitates glioma immune evasion by upregulating pd l1 expression |
| url | https://doi.org/10.1038/s41419-023-05878-x |
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