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Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen
Bai-Le Zuo1, Bo Yan2, Guo-Xu Zheng1
1State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China.
Abstract:
Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.
Insights
Engineered T cells using heregulin-1β (HRG1β) chimeric antigen receptors (CARs) effectively target HER3-positive breast cancer. This novel HRG1β-CAR T-cell therapy shows potent anti-tumor activity in vitro and in vivo, offering a new strategy against HER2-targeted therapy resistance.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Chimeric antigen receptor T-lymphocyte (CAR-T) therapy shows promise in cancer immunotherapy.
- Endogenous ligands may offer superior CAR efficacy and reduced immunogenicity compared to single-chain variable fragments.
- HER3/HER4 receptors are implicated in breast cancer progression and resistance to HER2-targeted therapies.
Purpose of the Study:
- To engineer T cells with a chimeric antigen receptor (CAR) utilizing the natural ligand heregulin-1β (HRG1β) for HER3/HER4.
- To evaluate the efficacy and specificity of HRG1β-CAR T cells against HER3-positive breast cancer models.
Main Methods:
- Construction of HRG1β-based CAR T cells.
- In vitro cytotoxicity assays using HER3-overexpressing breast cancer cell lines (SK-BR-3, BT-474).
- In vivo efficacy assessment in SK-BR-3 xenograft tumor models.
Main Results:
- Successful construction and transduction (50%) of HRG1β-CAR T cells.
- Specific recognition and killing of HER3-positive breast cancer cells in vitro.
- Significant tumoricidal effect observed in SK-BR-3 xenograft models.
Conclusions:
- HRG1β-based CAR T cells demonstrate effective suppression of HER family receptor-driven breast cancer.
- This approach presents a potential strategy to overcome resistance to existing HER2-targeted therapies.
- HRG1β-CAR T cells offer a novel therapeutic avenue for HER3-positive breast cancers.
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