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01-03-2018 | Original Article

Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor

Authors: Bai-Le Zuo, Bo Yan, Guo-Xu Zheng, Wen-Jin Xi, Xiao Zhang, An-Gang Yang, Lin-Tao Jia

Published in: Cancer Immunology, Immunotherapy | Issue 3/2018

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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Title: Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor
Authors: Bai-Le Zuo
Bo Yan
Guo-Xu Zheng
Wen-Jin Xi
Xiao Zhang
An-Gang Yang
Lin-Tao Jia
Publication date: 01-03-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 3/2018
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-017-2089-5

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Acknowledgements

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