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

JIE Xiao-liang, KONG Yang-yang, ZHOU Guang-biao

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.

 

Ключевые слова: CD47, SIRPα, опухоль, иммунотерапия.

 

Full Text:

PDF


References


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: 10.1136/bmj.k793.

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: 10.1186/s13045-016-0381-z.

JIANG Z, SUN H, YU J, et al. Targeting CD47 for cancer immunotherapy. J Hematol Oncol,2021,14(1): 180. doi: 10.1186/s13045-021-01197-w.

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: 10.1056/NEJMoa1807315.

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: 10. 1200/JCO.18.02018.Epub2019Feb27.

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: 10.1038/s41419-018-0601-2.

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: 10.7150/thno.40860. 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: 10.1136/jitc-2019-000413.

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: 10.1038/s41467-021-25475-w.

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: 10.3389/fimmu.2021. 732530.

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: 10.1073/pnas.1919702117.

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: 10. 1038/ncomms15494.

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: 10.7150/ijbs.60782.

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: 10.1007/s00432-022-04292-8.

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: 10.1016/j.prp.2018.10.021.

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: 10.1038/s41467-020-18245-7.

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: 10. 1038/s41419-018-1285-3.

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: 10.1080/2162402X.2017.1397248.

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: 10.3389/fimmu.2017.00404.

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: 10.1016/j.blre.2018.04.005. 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: 10.1016/j.tranon.2018.10.007.

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: 10.1007/s00428-018-2332-2.

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: 10.1007/s00262-020-02806-2. 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: 10.3389/fimmu.2021.768115. 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: 10. 1016/j.tranon.2020.100862.

DIZMAN N, BUCHBINDER E I. Cancer therapy targeting CD47/SIRPα. Cancers (Basel),2021,13(24): 6229. doi: 10.3390/cancers13246229. 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: 10.1016/j.bcp.2021.114894.

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: 10.1038/s41467-022-34064-4.

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: 10.1073/pnas.1718197115.

BETANCUR P A, ABRAHAM B J, YIU Y Y, et al. A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation


Refbacks

  • There are currently no refbacks.