Related Experiment Video
Updated: Aug 31, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
DLK1-directed chimeric antigen receptor T-cell therapy for hepatocellular carcinoma
Yangyang Zhai1, Kunyan He1, Liyu Huang1
1Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
Background:
Delta-like homologue 1 (DLK1), a transmembrane protein, is highly expressed in hepatocellular carcinoma (HCC). We explored whether DLK1-directed chimeric antigen receptor (CAR) T cells can specifically eliminate DLK1-positive HCC cells and serve as a therapeutic strategy for HCC immunotherapy.
Methods:
We first characterized a homemade anti-human DLK1 monoclonal antibody, sequenced the single-chain Fragment variable (scFv) and integrated it into the second-generation CAR lentiviral vector, and then developed the DLK1-directed CAR-T cells. The cytotoxic activities of DLK1-directed CAR-T cells against different HCC cells were evaluated in vitro and in vivo.
Results:
The genetically modified human T cells with the DLK1-directed CARs produced cytotoxic activity against DLK1-positive HCC cells. Additionally, the DLK1-directed CARs enhanced T cell proliferation and activation in a DLK1-dependent manner. Interestingly, the DLK1-targeted CAR-T cells significantly inhibited both subcutaneous and peritoneal xenograft tumours derived from human liver cancer cell lines HepG2 or Huh-7.
Conclusion:
DLK1-directed CAR-T cells specifically suppresses DLK1-positive HCC cells in vitro and in vivo. This study provides a novel transmembrane antigen DLK1 as a potential therapeutic target appropriate for CAR-T cell therapy, which may be further developed as a clinical therapeutic strategy for HCC immunotherapy.
Insights
Chimeric antigen receptor (CAR) T cells targeting Delta-like homologue 1 (DLK1) show promise for hepatocellular carcinoma (HCC) immunotherapy. These DLK1-directed CAR-T cells effectively eliminate DLK1-positive HCC cells in preclinical models.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Delta-like homologue 1 (DLK1) is a transmembrane protein overexpressed in hepatocellular carcinoma (HCC).
- HCC remains a significant global health challenge with limited effective immunotherapies.
Purpose of the Study:
- To investigate the efficacy of Delta-like homologue 1 (DLK1)-directed chimeric antigen receptor (CAR) T cells against HCC.
- To evaluate DLK1 as a potential therapeutic target for HCC immunotherapy.
Main Methods:
- Development of DLK1-directed CAR-T cells using a homemade anti-DLK1 antibody.
- Assessment of CAR-T cell cytotoxic activity against HCC cells in vitro and in vivo models.
Main Results:
- DLK1-directed CAR-T cells demonstrated specific cytotoxic activity against DLK1-positive HCC cells.
- Enhanced T cell proliferation and activation were observed in a DLK1-dependent manner.
- Significant inhibition of HCC xenograft tumors was achieved in vivo.
Conclusions:
- DLK1-directed CAR-T cells offer a targeted approach for suppressing DLK1-positive HCC.
- DLK1 represents a novel and promising target for developing CAR-T cell-based HCC immunotherapy.
