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Latest Findings on the Role of CD47 in Tumor Immune Evasion and Related Targeted Therapies
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摘要: CD47是一种免疫球蛋白，在多种癌细胞表面过表达。CD47与信号调节蛋白α（signal regulatory protein alpha, SIRPα）形成信号复合物，促使癌细胞从巨噬细胞介导的吞噬作用中逃逸。近年来，CD47已被证明在多种类型的实体肿瘤中高表达，并与患者的不良预后相关。越来越多的研究表明，抑制CD47-SIRPα信号通路可促进适应性免疫反应，增强巨噬细胞对肿瘤细胞的吞噬作用。人源化抗CD47 IgG4单克隆抗体已进入临床试验，用于多种进展期实体瘤和淋巴瘤的治疗，显示出其安全性并在部分患者中取得部分缓解的疗效。本综述描述了CD47的结构和功能以及肿瘤中调控CD47的机制，概述了靶向CD47的治疗性抗体药物的研究进展与其靶向药物较易发生严重不良反应的研究瓶颈，并评估了靶向CD47-SIRPα信号通路在抗癌治疗中的潜力。Abstract: CD47 is an immunoglobulin that is overexpressed on the surface of a variety of cancer cells. CD47 forms a signaling complex with signal regulatory protein alpha (SIRPα), prompting the escape of cancer cells from macrophage-mediated phagocytosis. In recent years, CD47 has been shown to be highly expressed in many types of solid tumors and is associated with poor prognosis in patients. More and more studies have shown that inhibition of the CD47-SIRPα signaling pathway can promote adaptive immune responses and enhance the phagocytosis of tumor cells by macrophages. Humanized anti-CD47 IgG4 monoclonal antibody has been studied in clinical trials for the treatment of a variety of advanced solid tumors and lymphomas, demonstrating a sound safety profile and achieving partial remission in some patients. In this review we discuss the structure and function of CD47 and the mechanism of CD47 regulation in tumors, summarize the research progress in therapeutic antibody drugs targeting CD47 and a bottleneck in research that targeted drugs are more prone to result in serious adverse effects, and evaluated the potential of the applying CD47-SIRPα signaling pathway in anti-cancer therapy.
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Key words:
- CD47 /
- SIRPα /
- Tumor /
- Immunotherapy
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图 1 肿瘤细胞CD47调控机制
Figure 1. Regulatory mechanism of CD47 in tumor cells
IL: interleukin; CD47: cluster of differentiation 47; SIRPα: signal regulatory protein alpha; LAT2: L-amino acid transporter 2; mTOR: mammalian target of rapamycin; QPCTL: glutaminyl-peptide cyclotransferase-like protein; c-MYC: v-myc avian myelocytomatosis viral oncogene homolog; SRSF10: serine and arginine-rich splicing factor 10; mIL1RAP: membrane form of interleukin-1 receptor accessory protein; DDB1: DNA binding protein 1; CUL4A: cullin 4A; HIF-1α: hypoxia-inducible factor-1α; NF-κB1: nuclear factor of kappa light polypeptide gene enhancer in B-cells 1.
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