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表皮生长因子受体（EGFR）靶向嵌合抗原受体（CAR）修饰的T细胞在体内和体外均能有效且特异性地抑制三阴性乳腺癌。

EGFR-targeted CAR-T cells are potent and specific in suppressing triple-negative breast cancer both and .

作者信息

Xia Lin, Zheng Zao-Zao, Liu Jun-Yi, Chen Yu-Jie, Ding Jian-Cheng, Xia Ning-Shao, Luo Wen-Xin, Liu Wen

机构信息

Fujian Provincial Key Laboratory of Innovative Drug Target Research School of Pharmaceutical Sciences Xiamen University Xiamen China.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics National Institute of Diagnostics and Vaccine Development in Infectious Diseases School of Public Health School of Life Sciences Xiamen University Xiamen China.

出版信息

Clin Transl Immunology. 2020 May 3;9(5):e01135. doi: 10.1002/cti2.1135. eCollection 2020 May.

DOI:10.1002/cti2.1135
PMID:32373345
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7196685/
Abstract

OBJECTIVES

Triple-negative breast cancer (TNBC) is well known for its strong invasiveness, rapid recurrence and poor prognosis. Immunotherapy, including chimeric antigen receptor-modified T (CAR-T) cells, has emerged as a promising tool to treat TNBC. The identification of a specific target tumor antigen and the design of an effective CAR are among the many challenges of CAR-T therapy.

METHODS

We reported that epidermal growth factor receptor (EGFR) is highly expressed in TNBC and consequently designed an optimal third generation of CAR targeting EGFR. The efficacy of primary T lymphocytes infected with EGFR CAR lentivirus (EGFR CAR-T) against TNBC was evaluated both and . The signalling pathways activated in tumor and EGFR CAR-T cells were revealed by RNA sequencing analysis.

RESULTS

Third-generation EGFR CAR-T cells exerted potent and specific suppression of TNBC cell growth , whereas limited cytotoxicity was observed towards normal breast epithelial cells or oestrogen receptor-positive breast cancer cells. This capability was further demonstrated in a xenograft mouse model, with minimal off-tumor cytotoxicity. Mechanistically, stimulation with TNBC cells induced the expansion of naïve-associated EGFR CAR-T cells and enhanced their persistence. Furthermore, EGFR CAR-T cells activated the interferon γ, granzyme-perforin-PARP and Fas-FADD-caspase signalling pathways in TNBC cells.

CONCLUSION

We demonstrate that EGFR is a relevant immunotherapeutic target in TNBC, and EGFR CAR-T exhibits potent and specific antitumor activity against TNBC, suggesting the potential of this third-generation EGFR CAR-T as an immunotherapy tool to treat TNBC in the clinic.

摘要

目的

三阴性乳腺癌（TNBC）以其强大的侵袭性、快速复发和不良预后而闻名。免疫疗法，包括嵌合抗原受体修饰的T（CAR-T）细胞，已成为治疗TNBC的一种有前景的工具。识别特定的靶肿瘤抗原和设计有效的CAR是CAR-T疗法面临的众多挑战之一。

方法

我们报道表皮生长因子受体（EGFR）在TNBC中高表达，因此设计了一种靶向EGFR的最佳第三代CAR。评估了感染EGFR CAR慢病毒的原代T淋巴细胞（EGFR CAR-T）对TNBC的疗效。通过RNA测序分析揭示了肿瘤细胞和EGFR CAR-T细胞中激活的信号通路。

结果

第三代EGFR CAR-T细胞对TNBC细胞生长具有强大且特异性的抑制作用，而对正常乳腺上皮细胞或雌激素受体阳性乳腺癌细胞观察到有限的细胞毒性。在异种移植小鼠模型中进一步证明了这种能力，肿瘤外细胞毒性最小。从机制上讲，用TNBC细胞刺激可诱导幼稚相关EGFR CAR-T细胞的扩增并增强其持久性。此外，EGFR CAR-T细胞激活了TNBC细胞中的干扰素γ、颗粒酶-穿孔素-PARP和Fas-FADD-半胱天冬酶信号通路。

结论

我们证明EGFR是TNBC中一个相关的免疫治疗靶点，EGFR CAR-T对TNBC表现出强大且特异性的抗肿瘤活性，表明这种第三代EGFR CAR-T作为一种免疫治疗工具在临床上治疗TNBC的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/d55ec657986f/CTI2-9-e1135-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/43d7245b0415/CTI2-9-e1135-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/f105f04a2635/CTI2-9-e1135-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/326703c65461/CTI2-9-e1135-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/206f1c6a6a53/CTI2-9-e1135-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/09fba1078416/CTI2-9-e1135-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/d55ec657986f/CTI2-9-e1135-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/43d7245b0415/CTI2-9-e1135-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/f105f04a2635/CTI2-9-e1135-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/326703c65461/CTI2-9-e1135-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/206f1c6a6a53/CTI2-9-e1135-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/09fba1078416/CTI2-9-e1135-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8a1/7196685/d55ec657986f/CTI2-9-e1135-g006.jpg

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