CD47

CD47 also known as integrin associated protein is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 and signal-regulatory protein alpha.

CD47-SIRPα interaction refers to the binding of the protein CD47 on the surface of a cell to the receptor protein SIRPα on the surface of another cell. This interaction is a critical “don't eat me” signal that allows healthy cells to evade phagocytosis (engulfment) by the immune system. CD47 is expressed on a variety of cells, including red blood cells, platelets, and cancer cells, while SIRPα is primarily expressed on macrophages and dendritic cells, which are immune cells that engulf and eliminate foreign or damaged cells.

The interaction between CD47 and SIRPα triggers a signaling cascade that inhibits phagocytosis. Specifically, the binding of CD47 to SIRPα results in the activation of a tyrosine phosphatase called SHP-1, which then inhibits downstream signaling pathways that would otherwise lead to phagocytosis. This allows healthy cells to avoid being mistakenly targeted and eliminated by the immune system.

However, this interaction can also be exploited by cancer cells, which often overexpress CD47 to evade detection and elimination by the immune system. Researchers are currently exploring therapeutic strategies that target the CD47-SIRPα interaction to enhance the immune system's ability to recognize and eliminate cancer cells.

Results show that blocking CD47-SIRPα in a PV mouse model due to either anti-CD47 treatment or loss of the inhibitory SIRPα-signal corrects the polycythemia phenotype. Anti-CD47 treatment marginally impacted PV RBC production while not influencing erythroid maturation. However, upon anti-CD47 treatment, high-parametric single-cell cytometry identified an increase of MerTK+ splenic monocyte-derived effector cells, which differentiate from Ly6Chi monocytes during inflammatory conditions, acquire an inflammatory phagocytic state. Furthermore, in vitro, functional assays showed that splenic JAK2 mutant macrophages were more “pro-phagocytic,” suggesting that PV RBCs exploit the CD47-SIRPα interaction to escape innate immune attacks by clonal JAK2 mutant macrophages ¹⁾.

CD47 is overexpressed in multiple tumours and plays an important role in immune escape and other biological processes of tumours. However, its role in adamantinomatous craniopharyngioma (ACP) remains unclear. Therefore, Zhang et al. from the Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China explored the functions of CD47 in ACP.

In this study, the expression of CD47 and the infiltration of immune cells in ACP was determined by immunohistochemistry (IHC) or immunofluorescence. Microglia-mediated phagocytosis was analysed using an in vitro phagocytosis assay. Using lentivirus transfection, CD47 was either silenced or overexpressed in primary ACP cells and the biological effects of CD47 on these cells were evaluated in vitro using cell viability, flow cytometry, wound healing, Transwell migration, and 3D hydrogel assays. The protein expression levels were analysed by western blotting.

Finger-like protrusions, which may be the key factor in the recurrence of ACP, were primarily found in the region of hypothalamic involvement. The expression of CD47 was higher in palisading epithelium compared to stellate reticulum and epithelial whorls. An in vitro phagocytosis assay showed that CD47 blockade could promote microglia-mediated phagocytosis. Functional assays revealed that CD47 promoted the growth, migration and invasion of ACP cells in vitro. Our mechanistic investigations showed that CD47 activated the MAPK/ERK pathway, thereby facilitating the biological behaviour of ACP cells.

Zhang et al. demonstrated that CD47 plays an important role in adamantinomatous craniopharyngioma cells, suggesting that CD47 could be a new potential therapeutic target for adamantinomatous craniopharyngioma treatment, and adding to the body of literature a role for the inhibition of MAPK/ERK in ACP ²⁾

Gholamin S, Mitra SS, Feroze AH, Liu J, Kahn SA, Zhang M, Esparza R, Richard C, Ramaswamy V, Remke M, Volkmer AK, Willingham S, Ponnuswami A, McCarty A, Lovelace P, Storm TA, Schubert S, Hutter G, Narayanan C, Chu P, Raabe EH, Harsh G 4th, Taylor MD, Monje M, Cho YJ, Majeti R, Volkmer JP, Fisher PG, Grant G, Steinberg GK, Vogel H, Edwards M, Weissman IL, Cheshier SH. Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci Transl Med. 2017 Mar 15;9(381). pii: eaaf2968. doi: 10.1126/scitranslmed.aaf2968. PubMed PMID: 28298418.

2: Feng M, Jiang W, Kim BYS, Zhang CC, Fu YX, Weissman IL. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer. 2019 Aug 28. doi: 10.1038/s41568-019-0183-z. [Epub ahead of print] Review. PubMed PMID: 31462760.

3: Chen S, Mei S, Hu X. Letter by Chen et al Regarding Article, “Enhancement of Hematoma Clearance With CD47 Blocking Antibody in Experimental Intracerebral Hemorrhage”. Stroke. 2019 Sep;50(9):e265. doi: 10.1161/STROKEAHA.119.026469. Epub 2019 Jul 10. PubMed PMID: 31288668.

4: Hua Y, Keep RF, Xi G. Response by Hua et al to Letter Regarding Article, “Enhancement of Hematoma Clearance With CD47 Blocking Antibody in Experimental Intracerebral Hemorrhage”. Stroke. 2019 Sep;50(9):e266. doi: 10.1161/STROKEAHA.119.026620. Epub 2019 Jul 10. PubMed PMID: 31288667; PubMed Central PMCID: PMC6710118.

5: Jing C, Bian L, Wang M, Keep RF, Xi G, Hua Y. Enhancement of Hematoma Clearance With CD47 Blocking Antibody in Experimental Intracerebral Hemorrhage. Stroke. 2019 Jun;50(6):1539-1547. doi: 10.1161/STROKEAHA.118.024578. Epub 2019 May 14. PubMed PMID: 31084334; PubMed Central PMCID: PMC6538472.

6: Ma D, Liu S, Lal B, Wei S, Wang S, Zhan D, Zhang H, Lee RS, Gao P, Lopez-Bertoni H, Ying M, Li JJ, Laterra J, Wilson MA, Xia S. Extracellular Matrix Protein Tenascin C Increases Phagocytosis Mediated by CD47 Loss of Function in Glioblastoma. Cancer Res. 2019 May 15;79(10):2697-2708. doi: 10.1158/0008-5472.CAN-18-3125. Epub 2019 Mar 21. PubMed PMID: 30898840.

7: Mohanty S, Yerneni K, Theruvath JL, Graef CM, Nejadnik H, Lenkov O, Pisani L, Rosenberg J, Mitra S, Cordero AS, Cheshier S, Daldrup-Link HE. Nanoparticle enhanced MRI can monitor macrophage response to CD47 mAb immunotherapy in osteosarcoma. Cell Death Dis. 2019 Jan 15;10(2):36. doi: 10.1038/s41419-018-1285-3. PubMed PMID: 30674867; PubMed Central PMCID: PMC6367456.

8: Hutter G, Theruvath J, Graef CM, Zhang M, Schoen MK, Manz EM, Bennett ML, Olson A, Azad TD, Sinha R, Chan C, Assad Kahn S, Gholamin S, Wilson C, Grant G, He J, Weissman IL, Mitra SS, Cheshier SH. Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma. Proc Natl Acad Sci U S A. 2019 Jan 15;116(3):997-1006. doi: 10.1073/pnas.1721434116. Epub 2019 Jan 2. PubMed PMID: 30602457; PubMed Central PMCID: PMC6338872.

9: Xie T, Liu B, Dai CG, Lu ZH, Dong J, Huang Q. Glioma stem cells reconstruct similar immunoinflammatory microenvironment in different transplant sites and induce malignant transformation of tumor microenvironment cells. J Cancer Res Clin Oncol. 2019 Feb;145(2):321-328. doi: 10.1007/s00432-018-2786-2. Epub 2018 Nov 10. PubMed PMID: 30415302.

10: Li F, Lv B, Liu Y, Hua T, Han J, Sun C, Xu L, Zhang Z, Feng Z, Cai Y, Zou Y, Ke Y, Jiang X. Blocking the CD47-SIRPα axis by delivery of anti-CD47 antibody induces antitumor effects in glioma and glioma stem cells. Oncoimmunology. 2017 Nov 6;7(2):e1391973. doi: 10.1080/2162402X.2017.1391973. eCollection 2018. PubMed PMID: 29308321; PubMed Central PMCID: PMC5749673.

11: Wu X, Luo X, Zhu Q, Zhang J, Liu Y, Luo H, Cheng Y, Xie Z. The Roles of Thrombospondins in Hemorrhagic Stroke. Biomed Res Int. 2017;2017:8403184. doi: 10.1155/2017/8403184. Epub 2017 Oct 30. Review. PubMed PMID: 29214179; PubMed Central PMCID: PMC5682909.

12: Gholamin S, Mitra SS, Feroze AH, Liu J, Kahn SA, Zhang M, Esparza R, Richard C, Ramaswamy V, Remke M, Volkmer AK, Willingham S, Ponnuswami A, McCarty A, Lovelace P, Storm TA, Schubert S, Hutter G, Narayanan C, Chu P, Raabe EH, Harsh G 4th, Taylor MD, Monje M, Cho YJ, Majeti R, Volkmer JP, Fisher PG, Grant G, Steinberg GK, Vogel H, Edwards M, Weissman IL, Cheshier SH. Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci Transl Med. 2017 Mar 15;9(381). pii: eaaf2968. doi: 10.1126/scitranslmed.aaf2968. PubMed PMID: 28298418.

13: Zhu H, Leiss L, Yang N, Rygh CB, Mitra SS, Cheshier SH, Weissman IL, Huang B, Miletic H, Bjerkvig R, Enger PØ, Li X, Wang J. Surgical debulking promotes recruitment of macrophages and triggers glioblastoma phagocytosis in combination with CD47 blocking immunotherapy. Oncotarget. 2017 Feb 14;8(7):12145-12157. doi: 10.18632/oncotarget.14553. PubMed PMID: 28076333; PubMed Central PMCID: PMC5355332.

14: Zhao S, Yu Z, Liu Y, Bai Y, Jiang Y, van Leyen K, Yang YG, Lok JM, Whalen MJ, Lo EH, Wang X. CD47 deficiency improves neurological outcomes of traumatic brain injury in mice. Neurosci Lett. 2017 Mar 16;643:125-130. doi: 10.1016/j.neulet.2016.12.006. Epub 2016 Dec 5. PubMed PMID: 27931776.

15: Mohme M, Riethdorf S, Pantel K. Circulating and disseminated tumour cells - mechanisms of immune surveillance and escape. Nat Rev Clin Oncol. 2017 Mar;14(3):155-167. doi: 10.1038/nrclinonc.2016.144. Epub 2016 Sep 20. Review. PubMed PMID: 27644321.

16: Kong X, Wang Y, Dai C, Ma W, Wang R. Is CD147 a New Biomarker Reflecting Histological Malignancy of Gliomas? Mol Neurobiol. 2017 Mar;54(2):1568-1576. doi: 10.1007/s12035-016-9894-2. Epub 2016 May 20. PubMed PMID: 27206428.

17: Qie Y, Yuan H, von Roemeling CA, Chen Y, Liu X, Shih KD, Knight JA, Tun HW, Wharen RE, Jiang W, Kim BY. Surface modification of nanoparticles enables selective evasion of phagocytic clearance by distinct macrophage phenotypes. Sci Rep. 2016 May 19;6:26269. doi: 10.1038/srep26269. Erratum in: Sci Rep. 2016 Aug 01;6:30663. PubMed PMID: 27197045; PubMed Central PMCID: PMC4872535.

18: Cao S, Zheng M, Hua Y, Chen G, Keep RF, Xi G. Hematoma Changes During Clot Resolution After Experimental Intracerebral Hemorrhage. Stroke. 2016 Jun;47(6):1626-31. doi: 10.1161/STROKEAHA.116.013146. Epub 2016 Apr 28. PubMed PMID: 27125525; PubMed Central PMCID: PMC5237112.

19: Sun FJ, Zhang CQ, Chen X, Wei YJ, Li S, Liu SY, Zang ZL, He JJ, Guo W, Yang H. Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex. J Neuroinflammation. 2016 Apr 19;13(1):85. doi: 10.1186/s12974-016-0546-2. PubMed PMID: 27095555; PubMed Central PMCID: PMC4837553.

20: Zhang M, Hutter G, Kahn SA, Azad TD, Gholamin S, Xu CY, Liu J, Achrol AS, Richard C, Sommerkamp P, Schoen MK, McCracken MN, Majeti R, Weissman I, Mitra SS, Cheshier SH. Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo. PLoS One. 2016 Apr 19;11(4):e0153550. doi: 10.1371/journal.pone.0153550. eCollection 2016. PubMed PMID: 27092773; PubMed Central PMCID: PMC4836698.

21: Ni W, Mao S, Xi G, Keep RF, Hua Y. Role of Erythrocyte CD47 in Intracerebral Hematoma Clearance. Stroke. 2016 Feb;47(2):505-11. doi: 10.1161/STROKEAHA.115.010920. Epub 2016 Jan 5. PubMed PMID: 26732568; PubMed Central PMCID: PMC4729651.

22: Yang SY, Choi SA, Lee JY, Park AK, Wang KC, Phi JH, Koh EJ, Park WY, Park SH, Hwang DW, Jung HW, Kim SK. miR-192 suppresses leptomeningeal dissemination of medulloblastoma by modulating cell proliferation and anchoring through the regulation of DHFR, integrins, and CD47. Oncotarget. 2015 Dec 22;6(41):43712-30. doi: 10.18632/oncotarget.6227. PubMed PMID: 26506238; PubMed Central PMCID: PMC4791261.

23: Park HW, Moon HE, Kim HS, Paek SL, Kim Y, Chang JW, Yang YS, Kim K, Oh W, Hwang JH, Kim JW, Kim DG, Paek SH. Human umbilical cord blood-derived mesenchymal stem cells improve functional recovery through thrombospondin1, pantraxin3, and vascular endothelial growth factor in the ischemic rat brain. J Neurosci Res. 2015 Dec;93(12):1814-25. doi: 10.1002/jnr.23616. Epub 2015 Sep 2. PubMed PMID: 26332684.

24: Zeiner PS, Preusse C, Blank AE, Zachskorn C, Baumgarten P, Caspary L, Braczynski AK, Weissenberger J, Bratzke H, Reiß S, Pennartz S, Winkelmann R, Senft C, Plate KH, Wischhusen J, Stenzel W, Harter PN, Mittelbronn M. MIF Receptor CD74 is Restricted to Microglia/Macrophages, Associated with a M1-Polarized Immune Milieu and Prolonged Patient Survival in Gliomas. Brain Pathol. 2015 Jul;25(4):491-504. doi: 10.1111/bpa.12194. Epub 2014 Nov 20. PubMed PMID: 25175718.

25: Zhou X, Xie Q, Xi G, Keep RF, Hua Y. Brain CD47 expression in a swine model of intracerebral hemorrhage. Brain Res. 2014 Jul 29;1574:70-6. doi: 10.1016/j.brainres.2014.06.003. Epub 2014 Jun 12. PubMed PMID: 24931767; PubMed Central PMCID: PMC4121112.

26: Xing B, Kong YG, Yao Y, Lian W, Wang RZ, Ren ZY. Study on the expression levels of CXCR4, CXCL12, CD44, and CD147 and their potential correlation with invasive behaviors of pituitary neuroendocrine tumors. Biomed Environ Sci. 2013 Jul;26(7):592-8. doi: 10.3967/0895-3988.2013.07.011. PubMed PMID: 23895705.

27: Peev NA, Tonchev AB, Penkowa M, Kalevski SK, Haritonov DG, Chaldakov GN. Cell proliferation index predicts relapse of brain metastases in non-irradiated patients. Acta Neurochir (Wien). 2008 Oct;150(10):1043-8; discussion 1048. doi: 10.1007/s00701-008-0020-8. Epub 2008 Sep 5. PubMed PMID: 18773139.