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Published on: February 21, 2025
Single-cell sequencing reveals VEGFR as a potential target for CAR-T cell therapy in chordoma
Huantong Wu1,2, Xinqiang Li3, Boyan Zhang1,2
1Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
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.
Insights
This study identifies Vascular Endothelial Growth Factor Receptor (VEGFR) as a promising target for Chordoma immunotherapy. Combining VEGFR-targeting with TGF-β modulation may enhance CAR-T cell therapy efficacy against this rare bone cancer.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Chordomas are rare bone tumors with poor outcomes upon recurrence.
- Identifying novel immunotherapeutic targets is crucial for improving chordoma treatment.
- This research focuses on cell surface proteins as potential targets.
Purpose of the Study:
- To identify novel immunotherapeutic targets for chordoma.
- To characterize cancer metastasis-related signaling pathways in chordoma.
- To evaluate the efficacy of engineered CAR-T cells against chordoma.
Main Methods:
- Single-cell RNA sequencing of 14 chordoma samples.
- Synthesis of VEGFR-targeting CAR-T cells and VEGFR/TGF-β scFv CAR-T cells.
- In vitro evaluation of CAR-T cell antitumor activity using cell lines and organoid models.
Main Results:
- VEGFR identified as a chordoma-specific antigen; TGF-β implicated in progression.
- Both VEGFR CAR-T and VEGFR/TGF-β scFv CAR-T cells demonstrated antitumor effects.
- VEGFR/TGF-β scFv CAR-T cells exhibited superior and sustained cytotoxicity in vitro.
Conclusions:
- Single-cell analysis reveals chordoma heterogeneity and TGF-β's role.
- VEGFR is a viable target for chordoma CAR-T cell therapy.
- Modulating TGF-β signaling alongside VEGFR targeting may enhance CAR-T cell efficacy.
