Unraveling the role of HDAC3 as an immunotherapy prognostic biomarker and therapeutic target in advanced non-small cell lung cancer
Abstract Background This study investigates HDAC3 as a potential immunotherapy biomarker in advanced non-small cell lung cancer (aNSCLC), focusing on its association with treatment response to immune checkpoint inhibitors (ICIs). Methods We employed a multi-phase approach in 78 aNSCLC patients with...
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BMC
2025-06-01
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| Series: | Respiratory Research |
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| Online Access: | https://doi.org/10.1186/s12931-025-03275-w |
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| author | Liyuan Dai Liling Huang Lin Li Le Tang Yuankai Shi Xiaohong Han |
| author_facet | Liyuan Dai Liling Huang Lin Li Le Tang Yuankai Shi Xiaohong Han |
| author_sort | Liyuan Dai |
| collection | DOAJ |
| description | Abstract Background This study investigates HDAC3 as a potential immunotherapy biomarker in advanced non-small cell lung cancer (aNSCLC), focusing on its association with treatment response to immune checkpoint inhibitors (ICIs). Methods We employed a multi-phase approach in 78 aNSCLC patients with 138 plasma samples, starting with a discovery phase that identified differential autoantibodies (AAbs) using proteomic analysis in responders and non-responders. In the validation phase, we assessed AAb levels at multiple time points. Additionally, immunohistochemistry and multiple immunofluorescence (n = 21) were used to validate HDAC3 expression in FFPE samples, single-cell RNA sequencing (n = 26) was performed to explore gene expression differences, cell and animal experiments were performed. Results We identified 127 differential AAbs, with five key AAbs (HDAC3, METTL21C, HSPB3, SPACA7, and SPPL2B) consistently linked to prognosis pre- and post-treatment (p < 0.05). A risk score model based on these AAbs effectively predicted progression-free survival. Furthermore, HDAC3 expression correlated with significant pathway enrichments and was associated with higher TGFβ1, PD-L1 infiltration and lower CD8+ T cells infiltration (p < 0.05). HDAC3 knockdown significantly inhibited cell proliferation, impaired colony formation, and induced G0/G1 phase arrest in lung cancer cells. Preclinical models demonstrated that RGFP966, an HDAC3 inhibitor, combined with anti–PD-1 therapy enhanced CD8+ T cell infiltration (p < 0.05). Conclusion Our findings underscore HDAC3’s role as a biomarker for predicting ICI response in aNSCLC and suggest its potential as a therapeutic target, paving the way for future studies on HDAC3-targeted therapies to improve immunotherapy outcomes. Clinical trial number not applicable. |
| format | Article |
| id | doaj-art-0764cbb02f064ebeb2db340d8bcaf712 |
| institution | DOAJ |
| issn | 1465-993X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | Respiratory Research |
| spelling | doaj-art-0764cbb02f064ebeb2db340d8bcaf7122025-08-20T03:21:02ZengBMCRespiratory Research1465-993X2025-06-0126111710.1186/s12931-025-03275-wUnraveling the role of HDAC3 as an immunotherapy prognostic biomarker and therapeutic target in advanced non-small cell lung cancerLiyuan Dai0Liling Huang1Lin Li2Le Tang3Yuankai Shi4Xiaohong Han5Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences & Peking Union Medical CollegeClinical Pharmacology Research Center,NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, Peking Union Medical College Hospital,Chinese Academy of Medical Sciences & Peking Union Medical CollegeAbstract Background This study investigates HDAC3 as a potential immunotherapy biomarker in advanced non-small cell lung cancer (aNSCLC), focusing on its association with treatment response to immune checkpoint inhibitors (ICIs). Methods We employed a multi-phase approach in 78 aNSCLC patients with 138 plasma samples, starting with a discovery phase that identified differential autoantibodies (AAbs) using proteomic analysis in responders and non-responders. In the validation phase, we assessed AAb levels at multiple time points. Additionally, immunohistochemistry and multiple immunofluorescence (n = 21) were used to validate HDAC3 expression in FFPE samples, single-cell RNA sequencing (n = 26) was performed to explore gene expression differences, cell and animal experiments were performed. Results We identified 127 differential AAbs, with five key AAbs (HDAC3, METTL21C, HSPB3, SPACA7, and SPPL2B) consistently linked to prognosis pre- and post-treatment (p < 0.05). A risk score model based on these AAbs effectively predicted progression-free survival. Furthermore, HDAC3 expression correlated with significant pathway enrichments and was associated with higher TGFβ1, PD-L1 infiltration and lower CD8+ T cells infiltration (p < 0.05). HDAC3 knockdown significantly inhibited cell proliferation, impaired colony formation, and induced G0/G1 phase arrest in lung cancer cells. Preclinical models demonstrated that RGFP966, an HDAC3 inhibitor, combined with anti–PD-1 therapy enhanced CD8+ T cell infiltration (p < 0.05). Conclusion Our findings underscore HDAC3’s role as a biomarker for predicting ICI response in aNSCLC and suggest its potential as a therapeutic target, paving the way for future studies on HDAC3-targeted therapies to improve immunotherapy outcomes. Clinical trial number not applicable.https://doi.org/10.1186/s12931-025-03275-wHDAC3AutoantibodyImmunotherapyPrognostic biomarkerNon-small cell lung cancer |
| spellingShingle | Liyuan Dai Liling Huang Lin Li Le Tang Yuankai Shi Xiaohong Han Unraveling the role of HDAC3 as an immunotherapy prognostic biomarker and therapeutic target in advanced non-small cell lung cancer Respiratory Research HDAC3 Autoantibody Immunotherapy Prognostic biomarker Non-small cell lung cancer |
| title | Unraveling the role of HDAC3 as an immunotherapy prognostic biomarker and therapeutic target in advanced non-small cell lung cancer |
| title_full | Unraveling the role of HDAC3 as an immunotherapy prognostic biomarker and therapeutic target in advanced non-small cell lung cancer |
| title_fullStr | Unraveling the role of HDAC3 as an immunotherapy prognostic biomarker and therapeutic target in advanced non-small cell lung cancer |
| title_full_unstemmed | Unraveling the role of HDAC3 as an immunotherapy prognostic biomarker and therapeutic target in advanced non-small cell lung cancer |
| title_short | Unraveling the role of HDAC3 as an immunotherapy prognostic biomarker and therapeutic target in advanced non-small cell lung cancer |
| title_sort | unraveling the role of hdac3 as an immunotherapy prognostic biomarker and therapeutic target in advanced non small cell lung cancer |
| topic | HDAC3 Autoantibody Immunotherapy Prognostic biomarker Non-small cell lung cancer |
| url | https://doi.org/10.1186/s12931-025-03275-w |
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