Targeting fibroblast activation protein with chimeric antigen receptor macrophages

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY Biochemical pharmacology Pub Date : 2024-11-01 DOI:10.1016/j.bcp.2024.116604

Yizhi Mao, Chen Yao, Shimeng Zhang, Qi Zeng, Jing Wang, Chunjie Sheng, Shuai Chen

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Abstract

Under the rapid advancement of chimeric antigen receptor T cell (CAR-T) technology, CAR-macrophages (CAR-Ms) are also being developed currently in the pre-clinical stage and have been shown to inhibit tumor growth in several mouse tumor models. Fibroblast activation protein (FAP) is a type II transmembrane serine protease, which is expressed in stromal fibroblasts of over 90 % of common human epithelial cancers and is upregulated in fibrotic diseases of the liver, lung and colon, etc. In this study, we firstly constructed FAP-CAR macrophages to target FAP⁺ cells through in vitro phagocytosis assays. In subsequent in vivo assays, we discovered that FAP-CAR-ΔZETA bone marrow-derived macrophages (BMDMs) rather than FAP-CAR BMDMs, exhibited a pronounced anti-tumor effect in mouse subcutaneous MC38 colon cancer model. In addition, FAP-CAR and FAP-CAR-ΔZETA BMDMs therapy could effectively improve CCl₄-induced liver fibrosis in mice. Collectively, CAR-Ms targeting FAP demonstrated great therapeutic potential in cancer and liver fibrosis therapy.

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用嵌合抗原受体巨噬细胞靶向成纤维细胞活化蛋白。

随着嵌合抗原受体 T 细胞（CAR-T）技术的快速发展，CAR-巨噬细胞（CAR-Ms）目前也处于临床前开发阶段，并已在多个小鼠肿瘤模型中显示出抑制肿瘤生长的作用。成纤维细胞活化蛋白（FAP）是一种Ⅱ型跨膜丝氨酸蛋白酶，在90%以上的常见人类上皮癌的基质成纤维细胞中表达，并在肝脏、肺部和结肠等纤维化疾病中上调。在本研究中，我们首先构建了 FAP-CAR 巨噬细胞，通过体外吞噬实验靶向 FAP+ 细胞。在随后的体内试验中，我们发现在小鼠皮下 MC38 结肠癌模型中，FAP-CAR-ΔZETA 骨髓衍生巨噬细胞（BMDMs）而非 FAP-CAR BMDMs 具有明显的抗肿瘤作用。此外，FAP-CAR 和 FAP-CAR-ΔZETA BMDMs 还能有效改善 CCl4 诱导的小鼠肝纤维化。总之，靶向FAP的CAR-Ms在癌症和肝纤维化治疗中展现出了巨大的治疗潜力。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.