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.
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Abbreviations
- ALL:
-
Acute lymphoblastic leukemia
- ARIA:
-
Acetylcholine receptor-inducing activity
- CFSE:
-
Carboxyfluorescein succinimidyl ester
- CLL:
-
Chronic lymphocytic leukemia
- EGF:
-
Epidermal growth factor
- HRG:
-
Heregulin
- HUVEC:
-
Human umbilical vein endothelial cell
- NDF:
-
Neu differentiation factor
- NRG:
-
Neuregulin
- PI:
-
Propidium iodide
- PVDF:
-
Polyvinylidene fluoride
- qRT-PCR:
-
Quantitative real-time polymerase chain reaction
- RT:
-
Room temperature
- SEM:
-
Standard error of mean
- SiRNA:
-
Small interfering RNA
- SMDF:
-
Sensory and motor neurons induced factor
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Acknowledgements
This work was supported by the National Natural Sciences Foundation of China (No. 81630069 and 81272646).
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Zuo, BL., Yan, B., Zheng, GX. et al. Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor. Cancer Immunol Immunother 67, 393–401 (2018). https://doi.org/10.1007/s00262-017-2089-5
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DOI: https://doi.org/10.1007/s00262-017-2089-5