Specific ECM degradation potentiates the antitumor activity of CAR-T cells in solid tumors.

IF 21.8 1区 医学 Q1 IMMUNOLOGY
Rui Zheng, Kuo Shen, Sixin Liang, Yanhong Lyu, Siyan Zhang, Hao Dong, Yuanfeng Li, Yujie Han, Xiaojuan Zhao, Yiting Zhang, Pengju Wang, Ruotong Meng, Shukun Bai, Jianxun Yang, Guofang Lu, Jia Li, Angang Yang, Rui Zhang, Bo Yan
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引用次数: 0

Abstract

Although major progress has been made in the use of chimeric antigen receptor (CAR)-T-cell therapy for hematological malignancies, this method is ineffective against solid tumors largely because of the limited infiltration, activation and proliferation of CAR-T cells. To overcome this issue, we engineered CAR-T cells with synthetic Notch (synNotch) receptors, which induce local tumor-specific secretion of extracellular matrix (ECM)-degrading enzymes at the tumor site. SynNotch CAR-T cells achieve precise ECM recognition and robustly kill targeted tumors, with synNotch-induced enzyme production enabling the degradation of components of the tumor ECM. In addition, this regulation strongly increased the infiltration of CAR-T cells and the clearance of solid tumors, resulting in tumor regression without toxicity in vivo. Notably, synNotch CAR-T cells also promoted the persistent activation of CAR-T cells in patient-derived tumor organoids. Thus, we constructed a synthetic T-cell system that increases the infiltration and antitumor function of CAR-T cells, providing a strategy for targeting ECM-rich solid tumors.

特异性 ECM 降解可增强 CAR-T 细胞在实体瘤中的抗肿瘤活性。
尽管在使用嵌合抗原受体(CAR)-T 细胞疗法治疗血液恶性肿瘤方面取得了重大进展,但这种方法对实体瘤的治疗效果不佳,主要原因是 CAR-T 细胞的浸润、活化和增殖能力有限。为了克服这一问题,我们设计了带有合成 Notch(synNotch)受体的 CAR-T 细胞,它能在肿瘤部位诱导局部肿瘤特异性分泌细胞外基质(ECM)降解酶。SynNotch CAR-T 细胞能精确识别 ECM,并强有力地杀死靶向肿瘤,SynNotch 诱导的酶分泌能降解肿瘤 ECM 的成分。此外,这种调控还能强烈增加 CAR-T 细胞的浸润和实体瘤的清除,从而在体内实现无毒性的肿瘤消退。值得注意的是,synNotch CAR-T 细胞还能促进 CAR-T 细胞在患者衍生的肿瘤组织细胞中持续活化。因此,我们构建了一种合成 T 细胞系统,它能增强 CAR-T 细胞的浸润和抗肿瘤功能,为靶向富含 ECM 的实体瘤提供了一种策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
31.20
自引率
1.20%
发文量
903
审稿时长
1 months
期刊介绍: Cellular & Molecular Immunology, a monthly journal from the Chinese Society of Immunology and the University of Science and Technology of China, serves as a comprehensive platform covering both basic immunology research and clinical applications. The journal publishes a variety of article types, including Articles, Review Articles, Mini Reviews, and Short Communications, focusing on diverse aspects of cellular and molecular immunology.
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