Integrative analysis of T cell-mediated tumor killing-related genes reveals KIF11 as a novel therapeutic target in esophageal squamous cell carcinoma
Abstract Background Immune checkpoint inhibitors (ICIs) are emerging promising agents for the treatment of patients with esophageal squamous cell carcinoma (ESCC), however, there are only a small proportion respond to ICI therapy. Therefore, selecting candidate patients who will benefit the most fro...
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BMC
2025-02-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06178-y |
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| author | Xinxin Cheng Huihui Zhao Zhangwang Li Liping Yan Qingjie Min Qingnan Wu Qimin Zhan |
| author_facet | Xinxin Cheng Huihui Zhao Zhangwang Li Liping Yan Qingjie Min Qingnan Wu Qimin Zhan |
| author_sort | Xinxin Cheng |
| collection | DOAJ |
| description | Abstract Background Immune checkpoint inhibitors (ICIs) are emerging promising agents for the treatment of patients with esophageal squamous cell carcinoma (ESCC), however, there are only a small proportion respond to ICI therapy. Therefore, selecting candidate patients who will benefit the most from these drugs is critical. However, validated biomarkers for predicting immunotherapy response and overall survival are lacking. As the fundamental principle of ICI therapy is T cell-mediated tumor killing (TTK), we aimed to develop a unique TTK-related gene prognostic index (TTKPI) for predicting survival outcomes and responses to immune-based therapy in ESCC patients. Methods Transcriptomic and clinical information of ESCC patients were from the GSE53625, GSE53624, GSE47404 and TCGA datasets. TTK-related genes were from the TISIDB database. The LASSO Cox regression model was employed to create the TTKPI. The prediction potential of the TTKPI was evaluated using the KM curve and time-dependent ROC curve analysis. Finally, the relationship between TTKPI and immunotherapy efficacy was investigated in clinical trials of ICIs (GSE91061, GSE135222, IMvigor210 cohort). The role of KIF11 in accelerating tumor progression was validated via a variety of functional experiments, including western blot, CCK-8, colony formation, wound healing scratch, and xenograft tumor model. The KIF11 expression was detected by multiplex fluorescent immunohistochemistry on tissue microarray from ESCC patients. Results We constructed the TTKPI based on 8 TTK-related genes. The TTKPI low-risk patients exhibited better overall survival. TTKPI was significantly and positively correlated with the main immune checkpoint molecules levels. Furthermore, the low-risk patients were more prone to reap the benefits of immunotherapy in the cohort undergoing anti-PD-L1 therapy. Moreover, we performed functional experiments on KIF11, which ranked as the most significant prognostic risk gene among the 8 TTK-related genes. Our findings identified that KIF11 knockdown significantly hindered cell proliferation and mobility in ESCC cells. The KIF11 expression was negatively related with CD8+ T cell infiltration in ESCC patient samples. Conclusions The TTKPI is a promising biomarker for accurately determining survival and predicting the effectiveness of immunotherapy in ESCC patients. This risk indicator can help patients receive timely and precise early intervention, thereby advancing personalized medicine and facilitating precise immuno-oncology research. KIF11 plays a crucial role in driving tumor proliferation and migration and may act as a potential tumor biomarker of ESCC. |
| format | Article |
| id | doaj-art-52bf5524deb74a658b120d6daa5463d4 |
| institution | OA Journals |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-52bf5524deb74a658b120d6daa5463d42025-08-20T02:15:11ZengBMCJournal of Translational Medicine1479-58762025-02-0123111610.1186/s12967-025-06178-yIntegrative analysis of T cell-mediated tumor killing-related genes reveals KIF11 as a novel therapeutic target in esophageal squamous cell carcinomaXinxin Cheng0Huihui Zhao1Zhangwang Li2Liping Yan3Qingjie Min4Qingnan Wu5Qimin Zhan6Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & InstituteDepartment of Medical Oncology and Department of Talent Highland, The First Affiliated Hospital of Xi’an Jiaotong UniversityKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & InstituteInstitute of Cytology and Genetics, Hengyang Medical College, University of South ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & InstituteAbstract Background Immune checkpoint inhibitors (ICIs) are emerging promising agents for the treatment of patients with esophageal squamous cell carcinoma (ESCC), however, there are only a small proportion respond to ICI therapy. Therefore, selecting candidate patients who will benefit the most from these drugs is critical. However, validated biomarkers for predicting immunotherapy response and overall survival are lacking. As the fundamental principle of ICI therapy is T cell-mediated tumor killing (TTK), we aimed to develop a unique TTK-related gene prognostic index (TTKPI) for predicting survival outcomes and responses to immune-based therapy in ESCC patients. Methods Transcriptomic and clinical information of ESCC patients were from the GSE53625, GSE53624, GSE47404 and TCGA datasets. TTK-related genes were from the TISIDB database. The LASSO Cox regression model was employed to create the TTKPI. The prediction potential of the TTKPI was evaluated using the KM curve and time-dependent ROC curve analysis. Finally, the relationship between TTKPI and immunotherapy efficacy was investigated in clinical trials of ICIs (GSE91061, GSE135222, IMvigor210 cohort). The role of KIF11 in accelerating tumor progression was validated via a variety of functional experiments, including western blot, CCK-8, colony formation, wound healing scratch, and xenograft tumor model. The KIF11 expression was detected by multiplex fluorescent immunohistochemistry on tissue microarray from ESCC patients. Results We constructed the TTKPI based on 8 TTK-related genes. The TTKPI low-risk patients exhibited better overall survival. TTKPI was significantly and positively correlated with the main immune checkpoint molecules levels. Furthermore, the low-risk patients were more prone to reap the benefits of immunotherapy in the cohort undergoing anti-PD-L1 therapy. Moreover, we performed functional experiments on KIF11, which ranked as the most significant prognostic risk gene among the 8 TTK-related genes. Our findings identified that KIF11 knockdown significantly hindered cell proliferation and mobility in ESCC cells. The KIF11 expression was negatively related with CD8+ T cell infiltration in ESCC patient samples. Conclusions The TTKPI is a promising biomarker for accurately determining survival and predicting the effectiveness of immunotherapy in ESCC patients. This risk indicator can help patients receive timely and precise early intervention, thereby advancing personalized medicine and facilitating precise immuno-oncology research. KIF11 plays a crucial role in driving tumor proliferation and migration and may act as a potential tumor biomarker of ESCC.https://doi.org/10.1186/s12967-025-06178-yESCCT cell-mediated tumor killingImmunotherapyPrognostic signatureKIF11 |
| spellingShingle | Xinxin Cheng Huihui Zhao Zhangwang Li Liping Yan Qingjie Min Qingnan Wu Qimin Zhan Integrative analysis of T cell-mediated tumor killing-related genes reveals KIF11 as a novel therapeutic target in esophageal squamous cell carcinoma Journal of Translational Medicine ESCC T cell-mediated tumor killing Immunotherapy Prognostic signature KIF11 |
| title | Integrative analysis of T cell-mediated tumor killing-related genes reveals KIF11 as a novel therapeutic target in esophageal squamous cell carcinoma |
| title_full | Integrative analysis of T cell-mediated tumor killing-related genes reveals KIF11 as a novel therapeutic target in esophageal squamous cell carcinoma |
| title_fullStr | Integrative analysis of T cell-mediated tumor killing-related genes reveals KIF11 as a novel therapeutic target in esophageal squamous cell carcinoma |
| title_full_unstemmed | Integrative analysis of T cell-mediated tumor killing-related genes reveals KIF11 as a novel therapeutic target in esophageal squamous cell carcinoma |
| title_short | Integrative analysis of T cell-mediated tumor killing-related genes reveals KIF11 as a novel therapeutic target in esophageal squamous cell carcinoma |
| title_sort | integrative analysis of t cell mediated tumor killing related genes reveals kif11 as a novel therapeutic target in esophageal squamous cell carcinoma |
| topic | ESCC T cell-mediated tumor killing Immunotherapy Prognostic signature KIF11 |
| url | https://doi.org/10.1186/s12967-025-06178-y |
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