Abstract
Background
Chordomas are rare osseous neoplasms with a dismal prognosis when they recur. Here we identified cell surface proteins that could potentially serve as novel immunotherapeutic targets in patients with chordoma.
Methods
Fourteen chordoma samples from patients attending Xuanwu Hospital Capital Medical University were subjected to single-cell RNA sequencing. Target molecules were identified on chordoma cells and cancer metastasis-related signalling pathways characterised. VEGFR-targeting CAR-T cells and VEGFR CAR-T cells with an additional TGF-β scFv were synthesised and their in vitro antitumor activities were evaluated, including in a primary chordoma organoid model.
Results
Single-cell transcriptome sequencing identified the chordoma-specific antigen VEGFR and TGF-β as therapeutic targets. VRGFR CAR-T cells and VEGFR/TGF-β scFv CAR-T cells recognised antigen-positive cells and exhibited significant antitumor effects through CAR-T cell activation and cytokine secretion. Furthermore, VEGFR/TGF-β scFv CAR-T cells showed enhanced and sustained cytotoxicity of chordoma cell lines in vitro compared with VRGFR CAR-T cells.
Conclusions
This study provides a comprehensive single-cell landscape of human chordoma and highlights its heterogeneity and the role played by TGF-β in chordoma progression. Our findings substantiate the potential of VEGFR as a target for CAR-T cell therapies in chordoma which, together with modulated TGF-β signalling, may augment the efficacy of CAR-T cells.
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Data availability
The datasets generated and analysed during this study are publicly accessible from the NGDC Genome Sequence Archive (https://ngdc.cncb.ac.cn/gsa-human/), accession number HRA006471.
Code availability
Additionally, the code utilised in our study is available from a dedicated GitHub repository, accessible at https://github.com/restore1997/chordoma2024.
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Funding
This work was supported by Beijing Natural Science Foundation Grant (L212039), National High Level Hospital Clinical Research Funding (2022-PUMCH-D-004), Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support (XMLX202138), The “Young Talents” Programme, supported by Beijing Municipal Hospital Administration (QML20210801), the Research and Application of Clinical Characteristic Diagnosis and Treatment Programme, Supported by Beijing Municipal Science & Technology Commission (Z221100007422019), and the CAMS Innovation Fund for Medical Sciences (CIFMS #2021-1-I2M-025).
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Zan Chen, Wanru Duan, Huantong Wu, and Xinqiang Li contributed to study’s conception and design. Huantong Wu, Xinqiang Li, Boyan Zhang, Penghao Liu, Maoyang Qi, Yueqi Du, Can Zhang performed the experiments and analysed the data. Zan Chen, Wanru Duan, Huantong Wu, Xinqiang Li, and Boyan Zhang wrote and revised the manuscript. All authors have read and agreed to the published version of the manuscript.
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This study was approved by the Medical Ethics Committee of Xuanwu Hospital, Capital Medical University, Beijing, China (Ethics Committee Approval No: [2021]021). Informed consent was obtained from all individual participants included in the study. The study was performed in accordance with the Declaration of Helsinki.
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Wu, H., Li, X., Zhang, B. et al. Single-cell sequencing reveals VEGFR as a potential target for CAR-T cell therapy in chordoma. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02635-5
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DOI: https://doi.org/10.1038/s41416-024-02635-5