CD47在肿瘤免疫逃逸中的作用及靶向治疗策略研究进展

揭晓亮; 孔阳阳; 周光飚

doi:10.12182/20230560101

CD47在肿瘤免疫逃逸中的作用及靶向治疗策略研究进展

doi:

我国癌病管理中心/koko体育app 临床医学科学的院良性癌肿医生分子结构良性癌肿学我国内容调查室（深圳 100021）

基金项目: 国家重点研发计划项目（No. 2020YFA0803300、No. 2022YFA1103900），国家自然科学基金重点项目（No. 81830093）和中国医学科学院知识创新工程人才引进与培养项目（No. 2022-RC310-05）资助

详细信息

作者简介:
周光飚，国家杰出青年科学基金获得者，中国医学科学院肿瘤医院分子肿瘤学国家重点实验室副主任，中国医学科学院北京协和医学院长聘教授。主要研究肺癌发生机理，包括利用多组学技术，在环境-基因互作、肿瘤微环境、肿瘤免疫与代谢层面，剖析机体内、外环境因素作用下肺癌的发生机理。在国际高水平期刊发表论文120篇，部分论文被F1000、Biocentury推荐。2009年起任中国工程院院刊Front Med杂志执行副主编

通讯作者:
E-mail：gbzhou@cicams.ac.cn

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出版历程
- 收稿日期: 2023-11-21
- 修回日期: 2024-02-15
- 网络出版日期: 2024-05-20
- 刊出日期: 2024-05-20

Latest Findings on the Role of CD47 in Tumor Immune Evasion and Related Targeted Therapies

State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China

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Corresponding author: E-mail: koko体育app:gbzhou@cicams.ac.cn

摘要

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。
- koko体育app: CD47 /
- 信号调节蛋白α /
- koko体育app: 肿瘤 /
- 免疫治疗
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.
- CD47 /
- SIRPα /
- koko体育app: Tumor /
- koko体育app: Immunotherapy

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图 1 肿瘤细胞CD47调控机制

Figure 1. Regulato🔴ry 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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koko体育app: 参考文献(50)

[1]	BAXI S, YANG A, GENNARELLI R L, et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ,2018,360: k793. doi:
[2]	LIU X, KWON H, LI Z, et al. Is CD47 an innate immune checkpoint for tumor evasion? J Hematol Oncol,2017,10(1): 12. doi:
[3]	JIANG Z, SUN H, YU J, et al. Targeting CD47 for cancer immunotherapy. J Hematol Oncol,2021,14(1): 180. doi:
[4]	ADVANI R, FLINN I, POPPLEWELL L, et al. CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin's Lymphoma. N Engl J Med,2018,379(18): 1711–1721. doi:
[5]	SIKIC B I, LAKHANI N, PATNAIK A, et al. First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers. J Clin Oncol,2019,37(12): 946–953. doi:
[6]	LEClAIR P, LIU C C, MONAJEMI M, et al. CD47-ligation induced cell death in T-acute lymphoblastic leukemia. Cell Death Dis,2018,9(5): 544. doi:
[7]	HU T, LIU H, LIANG Z, et al. Tumor-intrinsic CD47 signal regulates glycolysis and promotes colorectal cancer cell growth and metastasis. Theranostics,2020,10(9): 4056–4072. doi:
[8]	PELUSO M O, ADAM A, ARMET C M, et al. The Fully human anti-CD47 antibody SRF231 exerts dual-mechanism antitumor activity via engagement of the activating receptor CD32a. J Immunother Cancer,2020,8(1): e000413. doi:
[9]	FENARTI G, VILLANUEVA N, GRIFFITH M, et al. Structure of the human marker of self 5-transmembrane receptor CD47. Nat Commun,2021,12(1): 5218. doi:
[10]	DEHMANI S, NERR V, NEEL M, et al. SIRPγ-CD47 interaction positively regulates the activation of human T cells in situation of chronic stimulation. Front Immunol,2021,12: 732530. doi:
[11]	YAMASHIRO Y, THANG B Q, RAMIREZ K, et al. Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP in the vascular remodeling. Proc Natl Acad Sci U S A,2020,117(18): 9896–9905. doi:
[12]	KUMAR R, MICKAEL C, KASSA B, et al. TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension. Nat Commun,2017,8: 15494. doi:
[13]	JIA X, YAN B, TIAN X, et al. CD47/SIRPα pathway mediates cancer immune escape and immunotherapy. Int J Biol Sci,2021,17(13): 3281–3287. doi:
[14]	OZANIAK A, SMETANOVA J, BARTOLINI R, et al. A novel anti-CD47-targeted blockade promotes immune activation in human soft tissue sarcoma but does not potentiate anti-PD-1 blockade. J Cancer Res Clin Oncol,2022. doi:
[15]	YANG K, XU J, LIU Q, et al. Expression and significance of CD47, PD1 and PDL1 in T-cell acute lymphoblastic lymphoma/leukemia. Pathol Res Pract,2019,215(2): 265–271. doi:
[16]	CANDAS D, XIE B, HUANG J, et al. Dual blockade of CD47 and HER2 eliminates radioresistant breast cancer cells. Nat Commun,2020,11(1): 4591. doi:
[17]	MOHANTY S, YERNENI K, THERUVATH J L, et al. Nanoparticle enhanced MRI can monitor macrophage response to CD47 mAb immunotherapy in osteosarcoma. Cell Death Dis,2019,10(2): 36. doi:
[18]	WU L, YU G T, DENG W W, et al. Anti-CD47 treatment enhances anti-tumor T-cell immunity and improves immunosuppressive environment in head and neck squamous cell carcinoma. Oncoimmunology,2018,7(4): e1397248. doi:
[19]	LIU L, ZHANG L, YANG L, et al. Anti-CD47 antibody as a targeted therapeutic agent for human lung cancer and cancer stem cells. Front Immunol,2017,8: 404. doi:
[20]	RUSS A, HUA A B, MONTFORT W R, et al. Blocking "don't eat me" signal of CD47-SIRPα in hematological malignancies, an in-depth review. Blood Rev,2018,32(6): 480–489. doi:
[21]	VAETEEWOOTTACHARN K, KARIYA R, POTHIPAN P, et al. Attenuation of CD47-SIRPα signal in cholangiocarcinoma potentiates tumor-associated macrophage-mediated phagocytosis and suppresses intrahepatic metastasis. Transl Oncol,2019,12(2): 217–225. doi:
[22]	ABE H, SAITO R, ICHIMURA T, et al. CD47 expression in Epstein-Barr virus-associated gastric carcinoma: coexistence with tumor immunity lowering the ratio of CD8⁺/Foxp3⁺ T cells. Virchows Arch,2018,472(4): 643–651. doi:
[23]	SHI M, GU Y, JIN K, et al. CD47 expression in gastric cancer clinical correlates and association with macrophage infiltration. Cancer Immunol Immunother,2021,70(7): 1831–1840. doi:
[24]	YU L, DING Y, WAN T, et al. Significance of CD47 and its association with tumor immune microenvironment heterogeneity in ovarian cancer. Front Immunol,2021,12: 768115. doi:
[25]	HUANG C Y, YE Z H, HUANG M Y, et al. Regulation of CD47 expression in cancer cells. Transl Oncol,2020,13(12): 100862. doi:
[26]	DIZMAN N, BUCHBINDER E I. Cancer therapy targeting CD47/SIRPα. Cancers (Basel),2021,13(24): 6229. doi:
[27]	GONG J, JI Y, LIU X, et al. Mithramycin suppresses tumor growth by regulating CD47 and PD-L1 expression. Biochem Pharmacol,2022,197: 114894. doi:
[28]	WANG Z, LI B, LI S, et al. Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion. Nat Commun,2022,13(1): 6308. doi:
[29]	SAMANTA D, PARK Y, NI X, et al. Chemotherapy induces enrichment of CD47⁺/CD73⁺/PDL1⁺ immune evasive triple-negative breast cancer cells. Proc Natl Acad Sci U S A,2018,115(6): E1239–E1248. doi:
[30]	BETANCUR P A, ABRAHAM B J, YIU Y Y, et al. A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer. Nat Commun,2017,8: 14802. doi:
[31]	LIU F, DAI M, XU Q, et al. SRSF10-mediated IL1RAP alternative splicing regulates cervical cancer oncogenesis via mIL1RAP-NF-κB-CD47 axis. Oncogene,2018,37(18): 2394–2409. doi:
[32]	GOWDA P, PATRICK S, SINGH A, et al. Mutant isocitrate dehydrogenase 1 disrupts PKM2-β-Catenin-BRG1 transcriptional network-driven CD47 expression. Mol Cell Biol,2018,38(9): e00001–18. doi:
[33]	LI L, GONG Y, TANG J, et al. ZBTB28 inhibits breast cancer by activating IFNAR and dual blocking CD24 and CD47 to enhance macrophages phagocytosis. Cell Mol Life Sci,2022,79(2): 83. doi:
[34]	LOGTENBERG M E W, JANSEN J H M, RAABEN M, et al. Glutaminyl cyclase is an enzymatic modifier of the CD47-SIRPα axis and a target for cancer immunotherapy. Nat Med,2019,25(4): 612–619. doi:
[35]	YAO H, XU J. Regulation of cancer immune checkpoint: mono- and poly-ubiquitination: tags for fate. Adv Exp Med Biol,2020,1248: 295–324. doi:
[36]	ESMAILZADEH S, MANSOORI B, MOHAMMADI A, et al. Regulatory roles of micro-RNAs in T cell autoimmunity. Immunol Invest,2017,46(8): 864–879. doi:
[37]	RUPAIMOOLE R, SLACK F J. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov,2017,16(3): 203–222. doi:
[38]	HUANG W, WANG W T, FANG K, et al. MIR-708 promotes phagocytosis to eradicate T-ALL cells by targeting CD47. Mol Cancer,2018,17(1): 12. doi:
[39]	MOAZZENI H, NAJAFI A, KHANI M. Identification of direct target genes of miR-7, miR-9, miR-96, and miR-182 in the human breast cancer cell lines MCF-7 and MDA-MB-231. Mol Cell Probes,2017,34: 45–52. doi:
[40]	BEIZAVI Z, GHEIBIHAYAT S M, MOGHADASIAN H, et al. The regulation of CD47-SIRPα signaling axis by microRNAs in combination with conventional cytotoxic drugs together with the help of nano-delivery: a choice for therapy? Mol Biol Rep,2021,48(7): 5707–5722. doi:
[41]	XI Q, CHEN Y, YANG G Z, et al. miR-128 regulates tumor cell CD47 expression and promotes anti-tumor immunity in pancreatic cancer. Front Immunol,2020,11: 890. doi:
[42]	HAYAT S M G, BIANCONI V, PIRRO M, et al. CD47: role in the immune system and application to cancer therapy. Cell Oncol (Dordr),2020,43(1): 19–30. doi:
[43]	KAUDER S E, KUO T C, HARRABI O, et al. ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile. PLoS One,2018,13(8): e0201832. doi:
[44]	YU J, SONG Y, TIAN W. How to select IgG subclasses in developing anti-tumor therapeutic antibodies. J Hematol Oncol,2020,13(1): 45. doi:
[45]	QU T, ZHONG T, PANG X, et al. Ligufalimab, a novel anti-CD47 antibody with no hemagglutination demonstrates both monotherapy and combo antitumor activity. J Immunother Cancer,2022,10(11): e005517. doi:
[46]	XU Z, GAO J, YAO J, et al. Preclinical efficacy and toxicity studies of a highly specific chimeric anti-CD47 antibody. FEBS Open Bio,2021,11(3): 813–825. doi:
[47]	KÜLEY-BAGHERI Y, KREUZER K A, MONSEF I, et al. Effects of all-trans retinoic acid (ATRA) in addition to chemotherapy for adults with acute myeloid leukaemia (AML) (non-acute promyelocytic leukaemia (non-APL)). Cochrane Database Syst Rev,2018,8(8): CD011960. doi:
[48]	ANSELL S M, MARIS M B, LESOKHIN A M, et al. Phase Ⅰ study of the CD47 blocker TTI-621 in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res,2021,27(8): 2190–2199. doi:
[49]	PETROVA P S, VILLER N N, WONG M, et al. TTI-621 (SIRPαFc): a CD47-blocking innate immune checkpoint inhibitor with broad antitumor activity and minimal erythrocyte binding. Clin Cancer Res,2017,23(4): 1068–1079. doi:
[50]	PURO R J, BOUCHLAKA M N, HIEBSCH R R, et al. Development of AO-176, a Next-generation humanized anti-CD47 antibody with novel anticancer properties and negligible red blood cell binding. Mol Cancer Ther,2020,19(3): 835–846. doi: