KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC
Abstract Immunotherapy has become a prominent first-line cancer treatment strategy. In non-small cell lung cancer (NSCLC), the expression of PD-L1 induces an immuno-suppressive effect to protect cancer cells from immune elimination, which designates PD-L1 as an important target for immunotherapy. Ho...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06563-3 |
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| author | Jinghan Li Daiwang Shi Siyi Li Xiang Shi Yu Liu Yi Zhang Gebang Wang Chenlei Zhang Tian Xia Hai-long Piao Hong-Xu Liu |
| author_facet | Jinghan Li Daiwang Shi Siyi Li Xiang Shi Yu Liu Yi Zhang Gebang Wang Chenlei Zhang Tian Xia Hai-long Piao Hong-Xu Liu |
| author_sort | Jinghan Li |
| collection | DOAJ |
| description | Abstract Immunotherapy has become a prominent first-line cancer treatment strategy. In non-small cell lung cancer (NSCLC), the expression of PD-L1 induces an immuno-suppressive effect to protect cancer cells from immune elimination, which designates PD-L1 as an important target for immunotherapy. However, little is known about the regulation mechanism and the function of PD-L1 in lung cancer. In this study, we have discovered that KEAP1 serves as an E3 ligase to promote PD-L1 ubiquitination and degradation. We found that overexpression of KEAP1 suppressed tumor growth and promoted cytotoxic T-cell activation in vivo. These results indicate the important role of KEAP1 in anti-cancer immunity. Moreover, the combination of elevated KEAP1 expression with anti-PD-L1 immunotherapy resulted in a synergistic effect on both tumor growth and cytotoxic T-cell activation. Additionally, we found that the expressions of KEAP1 and PD-L1 were associated with NSCLC prognosis. In summary, our findings shed light on the mechanism of PD-L1 degradation and how NSCLC immune escape through KEAP1-PD-L1 signaling. Our results also suggest that KEAP1 agonist might be a potential clinical drug to boost anti-tumor immunity and improve immunotherapies in NSCLC. |
| format | Article |
| id | doaj-art-7f628e09e17f4d60891e9c3fea91ddce |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-7f628e09e17f4d60891e9c3fea91ddce2025-01-12T12:41:46ZengNature Publishing GroupCell Death and Disease2041-48892024-02-0115211410.1038/s41419-024-06563-3KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLCJinghan Li0Daiwang Shi1Siyi Li2Xiang Shi3Yu Liu4Yi Zhang5Gebang Wang6Chenlei Zhang7Tian Xia8Hai-long Piao9Hong-Xu Liu10Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteDepartment of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteDepartment of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteDepartment of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteDepartment of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteDepartment of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteDepartment of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteDepartment of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteDalian Institute of Chemical Physics, Chinese Academy of SciencesDepartment of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteDepartment of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteAbstract Immunotherapy has become a prominent first-line cancer treatment strategy. In non-small cell lung cancer (NSCLC), the expression of PD-L1 induces an immuno-suppressive effect to protect cancer cells from immune elimination, which designates PD-L1 as an important target for immunotherapy. However, little is known about the regulation mechanism and the function of PD-L1 in lung cancer. In this study, we have discovered that KEAP1 serves as an E3 ligase to promote PD-L1 ubiquitination and degradation. We found that overexpression of KEAP1 suppressed tumor growth and promoted cytotoxic T-cell activation in vivo. These results indicate the important role of KEAP1 in anti-cancer immunity. Moreover, the combination of elevated KEAP1 expression with anti-PD-L1 immunotherapy resulted in a synergistic effect on both tumor growth and cytotoxic T-cell activation. Additionally, we found that the expressions of KEAP1 and PD-L1 were associated with NSCLC prognosis. In summary, our findings shed light on the mechanism of PD-L1 degradation and how NSCLC immune escape through KEAP1-PD-L1 signaling. Our results also suggest that KEAP1 agonist might be a potential clinical drug to boost anti-tumor immunity and improve immunotherapies in NSCLC.https://doi.org/10.1038/s41419-024-06563-3 |
| spellingShingle | Jinghan Li Daiwang Shi Siyi Li Xiang Shi Yu Liu Yi Zhang Gebang Wang Chenlei Zhang Tian Xia Hai-long Piao Hong-Xu Liu KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC Cell Death and Disease |
| title | KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC |
| title_full | KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC |
| title_fullStr | KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC |
| title_full_unstemmed | KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC |
| title_short | KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC |
| title_sort | keap1 promotes anti tumor immunity by inhibiting pd l1 expression in nsclc |
| url | https://doi.org/10.1038/s41419-024-06563-3 |
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