Pathology Outlines

CD Markers
CD47

Authors: Frido Bruehl, M.D., Christian M. Schürch, M.D., Ph.D.

Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.

Minor changes: 16 June 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

PubMed Search: CD47[TI] review[PT]

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Table of Contents

Cite this page: Bruehl F, Schürch C. CD47. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cdmarkerscd47.html. Accessed July 7th, 2020.

Definition / general

CD47 is a ubiquitously expressed marker of self ("don't eat me" signal) and functions as an antiphagocytic molecule on the cell surface by binding the inhibitory molecule SIRPα on immune cells (e.g. macrophages) (Science 2000;288:2051)

Essential features

CD47 is expressed in most tissues and primarily acts as a marker of self
CD47 is overexpressed on solid tumors and hematolymphoid malignancies to evade immune control
CD47 has limited diagnostic utility but may be used as a prognostic or predictive marker in the future

Terminology

Integrin associated protein (IAP) (J Cell Biol 1990;111:2785)
Antigenic surface determinant protein OA3 (Biochem J 1994;304:525)
"Don't eat me" signal (Mol Immunol 2003;40:85)
Myeloid immune checkpoint (Nat Rev Clin Oncol 2019;16:275)

Pathophysiology

CD47 is a transmembrane protein and forms complexes with integrin αvβ3 and other integrins (J Cell Biol 1990;111:2785)
CD47 is a receptor for thrombospondin-1 and signal regulatory protein alpha (SIRPα) (J Biol Chem 1999;274:559, Blood 1999;94:3633)
Interaction of CD47 with SIRPα on macrophages and dendritic cells can downregulate immune cell activity by activating protein phosphatases such as SHP-1 and inhibiting cytokine synthesis (J Exp Med 1999;190:1175, J Immunol 2000;164:2193, J Immunol 2001;167:2547)
Red blood cells lacking CD47 are quickly eliminated from circulation by splenic macrophages (Leuk Lymphoma 2004;45:1319)
A complex mechanism involving conformational changes of the CD47-SIRPα complex has been suggested to impart a prophagocytic effect on red blood cells (Blood 2012;119:5512)
Calreticulin, a molecular chaperone and endoplasmatic reticulum protein, is expressed on the surface of stressed / senescent cells and cancer cells
- Calreticulin is the dominant prophagocytic ("eat me") signal on cancer cells and is counteracted by overexpression of CD47 (Sci Transl Med 2010;2:63ra94)
CD47 is also involved in platelet aggregation, epithelial and endothelial leukocyte adhesion, migration of immune cells and activation of T cells (Trends Cell Biol 2001;11:130)
Monoclonal anti-CD47 antibodies can reduce tumor cell growth in vitro, in xenograft tumor models and in vivo (Nat Med 1999;5:1277, Proc Natl Acad Sci U S A 2012;109:6662, PLoS One 2015;10:e0137345, Cell Death Dis 2018;9:544, N Engl J Med 2018;379:1711)

Diagrams / tables

Contributed by Frido Bruehl, M.D.

Proposed mechanism of action of CD47

Clinical features

Oncology
- CD47 is a promising therapeutic target and anti-CD47 therapies for advanced solid tumors and hematolymphoid malignancies are have reported preliminary results (N Engl J Med 2018;379:1711, J Clin Oncol 2019;37:946, Front Oncol 2020;9:1380)
- CD47 tumor expression is increased in response to chemotherapy (Proc Natl Acad Sci U S A 2018;115:E1239)
- CD47 tumor expression is decreased in response to radiotherapy (Int J Cancer 2013;133:120)
- CD47 expression in breast cancer is associated with response to trastuzumab therapy and poor prognosis (Proc Natl Acad Sci U S A 2011;108:18342, Oncol Lett 2019;18:3249)
Transfusion medicine
- CD47 is highly expressed on red blood cells and anti-CD47 therapy causes interferences with pretransfusion testing (Transfusion 2019;59:730)
- CD47 expression on stored red blood cells decreases over time (Transfus Apher Sci 2002;27:233)
- CD47 is increased in red blood cells in sickle cells patients in response to treatment with hydroxyurea (Haematologica 2008;93:502)

Interpretation

Cell membrane staining
Cytoplasmic staining may also be observed but the significance of this finding is unclear

Uses by pathologists

Cytological diagnosis of body cavity effusions: a 2 marker panel of CD47 (high expression) and BRCA1 associated protein 1 (BAP1; loss) can discriminate diffuse malignant mesothelioma from reactive pleural effusions with a sensitivity of 78% and a specificity of 100% (Oncoimmunology 2017;7:e1373235)

Prognostic factors

CD47 is overexpressed on circulating leukemia cells in acute myeloid leukemia and associated with a poor prognosis (Leuk Res 2015;39:749, Cell 2009;138:271, Cell 2009;138:286)
CD47 is overexpressed on acute lymphoblastic leukemia and associated with a poor prognosis (Cancer Res 2011;71:1374)
CD47 is overexpressed on non-Hodgkin B cell lymphomas and confers a worse prognosis (Cell 2010;142:699)
CD47 expression is a predictor of poor overall survival in ovarian carcinoma, glioma and glioblastoma (Proc Natl Acad Sci U S A 2012;109:6662)

Microscopic (histologic) images

Contributed by Christian M. Schürch, M.D., Ph.D.

Mesothelioma, cell block, CD47

Positive staining - normal

CD47 was first described in red blood cells and other hematopoietic cells (J Cell Biol 1990;111:2785)
CD47 is expressed in all tissue types based on mRNA studies and 4 splice variants with different tissue distribution are known (J Cell Sci 1995;108:3419)

Positive staining - disease

Cholangiocarcinoma (Transl Oncol 2019;12:217)
Colorectal carcinoma (Pathobiology 2019;86:182)
Gastric adenocarcinoma (Oncol Lett 2017;14:801)
Ovarian carcinoma (79.2%) (Gynecol Oncol 2016;143:393)
Endometrial carcinoma (J Immunol Res 2018;2018:6156757)
Small cell lung cancer (J Clin Invest 2016;126:2610)
Non small cell lung cancer (Cancer Med 2020;9:2390)
Mesothelioma (63%) (Oncoimmunology 2017;7:e1373235)
Anaplastic thyroid cancer (Thyroid 2019;29:979)
Squamous cell carcinoma of the head and neck (Int J Cancer 2013;133:120, Cells 2019;8:1658, Oncoimmunology 2018;7:e1397248)
Bladder cancer (Cent European J Urol 2017;70:349)
Breast cancer (Nat Commun 2017;8:14802)
Leiomyosarcoma (Proc Natl Acad Sci U S A 2012;109:6656)
Lymphoid malignancies (Cell 2010;142:699)
- Acute lymphoblastic leukemia (Cancer Res 2011;71:1374)
- Chronic lymphocytic leukemia (Nat Med 1999;5:1277)
- Hodgkin lymphoma (Clin Transl Oncol 2020;22:782)
- T cell lymphoma (Blood 2019;134:1430)
Myeloid malignancies
- Acute myeloid leukemia (Cell 2009;138:271, Cell 2009;138:286)
- Myelodysplastic syndrome (Leuk Res 2013;37:907)
- Chronic myelogenous leukemia (Cell 2009;138:271)
Myeloma (Leukemia 2012;26:2538)
Glioma and glioblastoma (Proc Natl Acad Sci U S A 2012;109:6662)
Atherogenesis is associated with increased CD47 expression (Arterioscler Thromb Vasc Biol 2008;28:615, Nature 2016;536:86)

Negative staining

Rh null red blood cells show a lack of CD47 on erythrocytes (Br J Haematol 2004;125:412)
CD47 expression is not increased in myeloproliferative neoplasm hematopoietic progenitor cells, such as in myelofibrosis, polycythemia vera and essential thrombocytosis (Braz J Med Biol Res 2018;52:e7784, Cell 2009;138:271)
Reduction in CD47 expression in monocytes is associated with disease severity in patients with burns (Burns 2011;37:94)

Sample pathology report

Pleural fluid, thoracentesis:
- Positive for malignant cells, favor mesothelioma (see comment)
- Comment: The cytology slide shows numerous three dimensional cell clusters and atypical single cells. Immunostains for calretinin, CK5/6, D2-40 and CD47 are positive. Immunostains for Ber-EP4, TTF1 and BAP1 are negative. The combined morphological and immunohistochemical features are consistent with an atypical mesothelial proliferation, favor malignant mesothelioma. Correlations with the clinical and imaging findings, as well as the patient history are necessary. A pleural biopsy may be valuable to further classify the disease process.

Additional references

OMIM: 601028 - CD47 Antigen [Accessed 10 June 2020]

Board review style question #1

Which statement about CD47, calreticulin and SIRPα is true?

Calreticulin is the dominant antiphagocytic protein
CD47 is an innate immune checkpoint and binds SIRPα
CD47 is a marker of activation
CD47 is negative in mesothelioma
CD47 is not expressed on red blood cells

Board review answer #1

B. CD47 is an innate immune checkpoint and binds SIRPα. CD47 can be thought of as an innate immune checkpoint and marker of self. Calreticulin is prophagocytic and its effect is controlled by the expression of CD47. Both molecules are highly expressed in mesothelioma and other cancer types. CD47 was first discovered in erythrocytes.

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Reference: CD47