The miR-23a/27a/24 − 2 cluster drives immune evasion and resistance to PD-1/PD-L1 blockade in non-small cell lung cancer
Abstract Programmed cell death protein ligand-1 (PD-L1) and major histocompatibility complex I (MHC-I) are key molecules related to tumor immune evasion and resistance to programmed cell death protein 1 (PD-1)/PD-L1 blockade. Here, we demonstrated that the upregulation of all miRNAs in the miR-23a/2...
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| Format: | Article |
| Language: | English |
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BMC
2024-12-01
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| Series: | Molecular Cancer |
| Online Access: | https://doi.org/10.1186/s12943-024-02201-w |
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| author | Hao Luo Bin Hu Xiang-Rong Gu Jing Chen Xiao-Qing Fan Wei Zhang Ren-Tao Wang Xian-Dong He Wei Guo Nan Dai Dan Jian Qing Li Cheng-Xiong Xu Hua Jin |
| author_facet | Hao Luo Bin Hu Xiang-Rong Gu Jing Chen Xiao-Qing Fan Wei Zhang Ren-Tao Wang Xian-Dong He Wei Guo Nan Dai Dan Jian Qing Li Cheng-Xiong Xu Hua Jin |
| author_sort | Hao Luo |
| collection | DOAJ |
| description | Abstract Programmed cell death protein ligand-1 (PD-L1) and major histocompatibility complex I (MHC-I) are key molecules related to tumor immune evasion and resistance to programmed cell death protein 1 (PD-1)/PD-L1 blockade. Here, we demonstrated that the upregulation of all miRNAs in the miR-23a/27a/24 − 2 cluster was correlated with poor survival, immune evasion and PD-1/PD-L1 blockade resistance in patients with non-small cell lung cancer (NSCLC). The overexpression of all miRNAs in the miR-23a/27a/24 − 2 cluster upregulated PD-L1 expression by targeting Cbl proto-oncogene B (CBLB) and downregulated MHC-I expression by increasing the level of eukaryotic initiation factor 3B (eIF3B) via the targeting of microphthalmia-associated transcription factor (MITF). In addition, we demonstrated that the expression of the miR-23a/27a/24 − 2 cluster of miRNAs is maintained in NSCLC through increased Wnt/β-catenin signaling-regulated interaction of transcription factor 4 (TCF4) and the miR-23a/27a/24 − 2 cluster promoter. Notably, pharmacologic targeting of the eIF3B pathway dramatically increased sensitivity to PD-1/PD-L1 blockade in patients with high expression of the miR-23a/27a/24 − 2 cluster in NSCLC. This effect was achieved by increasing MHC-I expression while maintaining high expression of PD-L1 induced by the miR-23a/27a/24 − 2 cluster. In summary, we elucidate the mechanism by which the miR-23a/27a/24 − 2 cluster miRNAs maintain their own expression and the molecular mechanism by which the miR-23a/27a/24 − 2 cluster miRNAs promote tumor immune evasion and PD-1/PD-L1 blockade resistance. In addition, we provide a novel strategy for the treatment of NSCLC expressing high levels of the miR-23a/27a/24 − 2 cluster. |
| format | Article |
| id | doaj-art-5a64ad5347ae42d3bf4106b9d37f009e |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-5a64ad5347ae42d3bf4106b9d37f009e2025-01-05T12:10:21ZengBMCMolecular Cancer1476-45982024-12-0123111510.1186/s12943-024-02201-wThe miR-23a/27a/24 − 2 cluster drives immune evasion and resistance to PD-1/PD-L1 blockade in non-small cell lung cancerHao Luo0Bin Hu1Xiang-Rong Gu2Jing Chen3Xiao-Qing Fan4Wei Zhang5Ren-Tao Wang6Xian-Dong He7Wei Guo8Nan Dai9Dan Jian10Qing Li11Cheng-Xiong Xu12Hua Jin13Department of Thoracic Surgery, Daping Hospital, Army Medical UniversityDepartment of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Medicine School of University of Electronic Science and TechnologyDepartment of Radiology, Daping Hospital, Army Military Medical UniversitySchool of Medicine, Chongqing UniversityDepartment of Thoracic Surgery, Daping Hospital, Army Medical UniversityDepartment of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Medicine School of University of Electronic Science and TechnologyCollege of Pulmonary and Critical Care Medicine, Chinese PLA General HospitalDepartment of Thoracic Surgery, Daping Hospital, Army Medical UniversityDepartment of Thoracic Surgery, Daping Hospital, Army Medical UniversityCancer Center, Daping Hospital, Army Medical UniversityCancer Center, Daping Hospital, Army Medical UniversityThe Shapingba Hospital, Chongqing UniversitySchool of Medicine, Chongqing UniversityDepartment of Thoracic Surgery, Daping Hospital, Army Medical UniversityAbstract Programmed cell death protein ligand-1 (PD-L1) and major histocompatibility complex I (MHC-I) are key molecules related to tumor immune evasion and resistance to programmed cell death protein 1 (PD-1)/PD-L1 blockade. Here, we demonstrated that the upregulation of all miRNAs in the miR-23a/27a/24 − 2 cluster was correlated with poor survival, immune evasion and PD-1/PD-L1 blockade resistance in patients with non-small cell lung cancer (NSCLC). The overexpression of all miRNAs in the miR-23a/27a/24 − 2 cluster upregulated PD-L1 expression by targeting Cbl proto-oncogene B (CBLB) and downregulated MHC-I expression by increasing the level of eukaryotic initiation factor 3B (eIF3B) via the targeting of microphthalmia-associated transcription factor (MITF). In addition, we demonstrated that the expression of the miR-23a/27a/24 − 2 cluster of miRNAs is maintained in NSCLC through increased Wnt/β-catenin signaling-regulated interaction of transcription factor 4 (TCF4) and the miR-23a/27a/24 − 2 cluster promoter. Notably, pharmacologic targeting of the eIF3B pathway dramatically increased sensitivity to PD-1/PD-L1 blockade in patients with high expression of the miR-23a/27a/24 − 2 cluster in NSCLC. This effect was achieved by increasing MHC-I expression while maintaining high expression of PD-L1 induced by the miR-23a/27a/24 − 2 cluster. In summary, we elucidate the mechanism by which the miR-23a/27a/24 − 2 cluster miRNAs maintain their own expression and the molecular mechanism by which the miR-23a/27a/24 − 2 cluster miRNAs promote tumor immune evasion and PD-1/PD-L1 blockade resistance. In addition, we provide a novel strategy for the treatment of NSCLC expressing high levels of the miR-23a/27a/24 − 2 cluster.https://doi.org/10.1186/s12943-024-02201-w |
| spellingShingle | Hao Luo Bin Hu Xiang-Rong Gu Jing Chen Xiao-Qing Fan Wei Zhang Ren-Tao Wang Xian-Dong He Wei Guo Nan Dai Dan Jian Qing Li Cheng-Xiong Xu Hua Jin The miR-23a/27a/24 − 2 cluster drives immune evasion and resistance to PD-1/PD-L1 blockade in non-small cell lung cancer Molecular Cancer |
| title | The miR-23a/27a/24 − 2 cluster drives immune evasion and resistance to PD-1/PD-L1 blockade in non-small cell lung cancer |
| title_full | The miR-23a/27a/24 − 2 cluster drives immune evasion and resistance to PD-1/PD-L1 blockade in non-small cell lung cancer |
| title_fullStr | The miR-23a/27a/24 − 2 cluster drives immune evasion and resistance to PD-1/PD-L1 blockade in non-small cell lung cancer |
| title_full_unstemmed | The miR-23a/27a/24 − 2 cluster drives immune evasion and resistance to PD-1/PD-L1 blockade in non-small cell lung cancer |
| title_short | The miR-23a/27a/24 − 2 cluster drives immune evasion and resistance to PD-1/PD-L1 blockade in non-small cell lung cancer |
| title_sort | mir 23a 27a 24 2 cluster drives immune evasion and resistance to pd 1 pd l1 blockade in non small cell lung cancer |
| url | https://doi.org/10.1186/s12943-024-02201-w |
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