IL-21和CXCL9-工程化GPC3特异性CAR-T细胞与PD-1阻断结合可增强对肝细胞癌的细胞毒活性。

IF 3.2 4区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Shanshan Chen, Fusheng Gong, Shijia Liu, Yunqing Xie, Xingming Ye, Xiaowei Lin, Xiangru Wang, Qiuhong Zheng, Qinying Liu, Yang Sun
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引用次数: 0

摘要

CAR-T细胞在实体瘤中的应用面临着一些挑战,包括T细胞归巢能力差、T细胞浸润有限以及免疫抑制性肿瘤环境。在这项研究中,我们开发了一种新方法来解决这些障碍,即设计共同表达 IL-21 和 CXCL9 的 GPC3 特异性 CAR-T 细胞(21 × 9 GPC3 CAR-T 细胞),并阻断其上的 PD-1 表达。我们在体外评估了所述 CAR-T 细胞的增殖、细胞表型、细胞因子分泌和细胞迁移。在体外和体内检测了基因工程 CAR-T 细胞的细胞毒活性。与传统的 GPC3 CAR-T 细胞相比,21 × 9 GPC3 CAR-T 细胞在体外表现出更强的增殖、细胞因子分泌和趋化能力。此外,当 21 × 9 GPC3 CAR-T 细胞与 PD-1 阻断结合使用时,其增殖、细胞因子分泌和效应 T 细胞(如 CTL、NKT 和 TEM 细胞)富集能力均有所增强。在异种移植肿瘤模型中,PD-1阻断的21 × 9 GPC3 CAR-T细胞有效抑制了HCC异种移植的生长,并增加了T细胞浸润。总之,我们的研究成功生成了同时表达IL-21和CXCL9的GPC3 CAR-T细胞,证明了结合PD-1阻断可通过促进增殖、细胞因子分泌、趋化和抗肿瘤活性进一步增强CAR-T细胞的功能。这些发现为GPC3阳性的HCC患者提供了一种充满希望且可能有效的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

IL-21- and CXCL9-engineered GPC3-specific CAR-T cells combined with PD-1 blockade enhance cytotoxic activities against hepatocellular carcinoma.

IL-21- and CXCL9-engineered GPC3-specific CAR-T cells combined with PD-1 blockade enhance cytotoxic activities against hepatocellular carcinoma.

The application of CAR-T cells in solid tumors poses several challenges, including poor T cell homing ability, limited infiltration of T cells and an immunosuppressive tumor environment. In this study, we developed a novel approach to address these obstacles by designing GPC3-specific CAR-T cell that co-express IL-21 and CXCL9 (21 × 9 GPC3 CAR-T cells) and blocking the PD-1 expression on it. The proliferation, cell phenotype, cytokine secretion and cell migration of indicated CAR-T cells were evaluated in vitro. The cytotoxic activities of genetically engineered CAR-T cells were accessed in vitro and in vivo. Compared to conventional GPC3 CAR-T cells, the 21 × 9 GPC3 CAR-T cells demonstrated superior proliferation, cytokine secretion and chemotaxis capabilities in vitro. Furthermore, when combined with PD-1 blockade, the 21 × 9 GPC3 CAR-T cells exhibited enhanced proliferation, cytokine secretion and enrichment of effector T cells such as CTL, NKT and TEM cells. In xenograft tumor models, the PD-1 blocked 21 × 9 GPC3 CAR-T cells effectively suppressed HCC xenograft growth and increased T cell infiltration. Overall, our study successfully generated GPC3 CAR-T cells expressing both IL-21 and CXCL9, demonstrated that combining PD-1 blockade can further enhance CAR-T cell function by promoting proliferation, cytokine secretion, chemotaxis and antitumor activity. These findings present a hopeful and potentially effective strategy for GPC3-positive HCC patients.

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来源期刊
Clinical and Experimental Medicine
Clinical and Experimental Medicine 医学-医学:研究与实验
CiteScore
4.80
自引率
2.20%
发文量
159
审稿时长
2.5 months
期刊介绍: Clinical and Experimental Medicine (CEM) is a multidisciplinary journal that aims to be a forum of scientific excellence and information exchange in relation to the basic and clinical features of the following fields: hematology, onco-hematology, oncology, virology, immunology, and rheumatology. The journal publishes reviews and editorials, experimental and preclinical studies, translational research, prospectively designed clinical trials, and epidemiological studies. Papers containing new clinical or experimental data that are likely to contribute to changes in clinical practice or the way in which a disease is thought about will be given priority due to their immediate importance. Case reports will be accepted on an exceptional basis only, and their submission is discouraged. The major criteria for publication are clarity, scientific soundness, and advances in knowledge. In compliance with the overwhelmingly prevailing request by the international scientific community, and with respect for eco-compatibility issues, CEM is now published exclusively online.
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