Genetic and transcriptional insights into immune checkpoint blockade response and survival: lessons from melanoma and beyond
Abstract Background Integration of immune checkpoint inhibitors (ICIs) with non-immune therapies relies on identifying combinatorial biomarkers, which are essential for patient stratification and personalized treatment. Methods We analyzed genomic and transcriptomic data from pretreatment tumor samp...
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BMC
2025-04-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06467-6 |
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| author | Jiaxin Wen Yanfeng Wang Song Wang Yuxin Liang Xiaozhen Hu Qiuxiang Ou Hua Bao Kuo Zhao Youyu Wang |
| author_facet | Jiaxin Wen Yanfeng Wang Song Wang Yuxin Liang Xiaozhen Hu Qiuxiang Ou Hua Bao Kuo Zhao Youyu Wang |
| author_sort | Jiaxin Wen |
| collection | DOAJ |
| description | Abstract Background Integration of immune checkpoint inhibitors (ICIs) with non-immune therapies relies on identifying combinatorial biomarkers, which are essential for patient stratification and personalized treatment. Methods We analyzed genomic and transcriptomic data from pretreatment tumor samples of 342 melanoma patients treated with ICIs to identify mutations and expression signatures associated with ICI response and survival. External validation and mechanistic exploratory analyses were conducted in two additional datasets to assess generalizability. Results Responders were more likely to have received anti-PD-1 therapy rather than anti-CTLA-4 and exhibited a higher tumor mutation burden (both P < 0.001). Mutations in the dynein axonemal heavy chain (DNAH) family genes, specifically DNAH2 (P = 0.03), DNAH6 (P < 0.001), and DNAH9 (P < 0.01), were enriched in responders. The combined mutational status of DNAH 2/6/9 effectively stratified patients by progression-free survival (hazard ratio [HR]: 0.69; 95% confidence interval [CI] 0.51–0.92; P = 0.013) and overall survival (HR: 0.58; 95% CI 0.43–0.78; P < 0.001), with consistent association observed in the validation cohort (HR: 0.28; 95% CI 0.12–0.61; P < 0.001). DNAH-altered melanomas exhibited upregulation of chemokine signaling, cytokine-cytokine receptor interaction, and cell cycle-related pathways, along with elevated expression of immune-related signatures in interferon signaling, cytolytic activity, T cell function, and immune checkpoints. Using LASSO logistic regression, we identified a 26-gene composite signature predictive of clinical response, achieving an area under the curve (AUC) of 0.880 (95% CI 0.825–0.936) in the training dataset and 0.725 (95% CI 0.595–0.856) in the testing dataset. High-risk patients, stratified by the expression levels of a 13-gene signature, demonstrated significantly shorter overall survival in both datasets (HR: 3.35; P < 0.001; HR: 2.93; P = 0.002). Conclusions This analysis identified potential molecular determinants of response and survival to ICI treatment. Insights from melanoma biomarker research hold significant promise for translation into other malignancies, guiding individualized anti-tumor immunotherapy. |
| format | Article |
| id | doaj-art-c040f18ee7444db2b7668770bb080787 |
| institution | OA Journals |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-04-01 |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-c040f18ee7444db2b7668770bb0807872025-08-20T02:20:01ZengBMCJournal of Translational Medicine1479-58762025-04-0123111410.1186/s12967-025-06467-6Genetic and transcriptional insights into immune checkpoint blockade response and survival: lessons from melanoma and beyondJiaxin Wen0Yanfeng Wang1Song Wang2Yuxin Liang3Xiaozhen Hu4Qiuxiang Ou5Hua Bao6Kuo Zhao7Youyu Wang8Department of Thoracic Surgery, Chinese PLA General HospitalDepartment of Pathology, Beidahuang Industry Group General HospitalGeneseeq Research Institute, Nanjing Geneseeq Technology IncDepartment of Pathology, Lanzhou University Second HospitalDepartment of Scientific Affairs, Mabwell (Shanghai) Biotech Co., Ltd.Geneseeq Research Institute, Nanjing Geneseeq Technology IncGeneseeq Research Institute, Nanjing Geneseeq Technology IncDay Care Ward, Tianjin Cancer Hospital Airport HospitalDepartment of Thoracic Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaAbstract Background Integration of immune checkpoint inhibitors (ICIs) with non-immune therapies relies on identifying combinatorial biomarkers, which are essential for patient stratification and personalized treatment. Methods We analyzed genomic and transcriptomic data from pretreatment tumor samples of 342 melanoma patients treated with ICIs to identify mutations and expression signatures associated with ICI response and survival. External validation and mechanistic exploratory analyses were conducted in two additional datasets to assess generalizability. Results Responders were more likely to have received anti-PD-1 therapy rather than anti-CTLA-4 and exhibited a higher tumor mutation burden (both P < 0.001). Mutations in the dynein axonemal heavy chain (DNAH) family genes, specifically DNAH2 (P = 0.03), DNAH6 (P < 0.001), and DNAH9 (P < 0.01), were enriched in responders. The combined mutational status of DNAH 2/6/9 effectively stratified patients by progression-free survival (hazard ratio [HR]: 0.69; 95% confidence interval [CI] 0.51–0.92; P = 0.013) and overall survival (HR: 0.58; 95% CI 0.43–0.78; P < 0.001), with consistent association observed in the validation cohort (HR: 0.28; 95% CI 0.12–0.61; P < 0.001). DNAH-altered melanomas exhibited upregulation of chemokine signaling, cytokine-cytokine receptor interaction, and cell cycle-related pathways, along with elevated expression of immune-related signatures in interferon signaling, cytolytic activity, T cell function, and immune checkpoints. Using LASSO logistic regression, we identified a 26-gene composite signature predictive of clinical response, achieving an area under the curve (AUC) of 0.880 (95% CI 0.825–0.936) in the training dataset and 0.725 (95% CI 0.595–0.856) in the testing dataset. High-risk patients, stratified by the expression levels of a 13-gene signature, demonstrated significantly shorter overall survival in both datasets (HR: 3.35; P < 0.001; HR: 2.93; P = 0.002). Conclusions This analysis identified potential molecular determinants of response and survival to ICI treatment. Insights from melanoma biomarker research hold significant promise for translation into other malignancies, guiding individualized anti-tumor immunotherapy.https://doi.org/10.1186/s12967-025-06467-6Immune checkpoint inhibitorClinical responseBiomarkerDNAHGene expression |
| spellingShingle | Jiaxin Wen Yanfeng Wang Song Wang Yuxin Liang Xiaozhen Hu Qiuxiang Ou Hua Bao Kuo Zhao Youyu Wang Genetic and transcriptional insights into immune checkpoint blockade response and survival: lessons from melanoma and beyond Journal of Translational Medicine Immune checkpoint inhibitor Clinical response Biomarker DNAH Gene expression |
| title | Genetic and transcriptional insights into immune checkpoint blockade response and survival: lessons from melanoma and beyond |
| title_full | Genetic and transcriptional insights into immune checkpoint blockade response and survival: lessons from melanoma and beyond |
| title_fullStr | Genetic and transcriptional insights into immune checkpoint blockade response and survival: lessons from melanoma and beyond |
| title_full_unstemmed | Genetic and transcriptional insights into immune checkpoint blockade response and survival: lessons from melanoma and beyond |
| title_short | Genetic and transcriptional insights into immune checkpoint blockade response and survival: lessons from melanoma and beyond |
| title_sort | genetic and transcriptional insights into immune checkpoint blockade response and survival lessons from melanoma and beyond |
| topic | Immune checkpoint inhibitor Clinical response Biomarker DNAH Gene expression |
| url | https://doi.org/10.1186/s12967-025-06467-6 |
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