Abstract

Simple SummaryThe immune system is the first line of protection against infected and tumor cells. Macrophages are specialized immune cells that recognize these abnormal cells and eliminate them by a mechanism called phagocytosis. All normal cells express a protein called CD47 or “don’t eat me signal” to prevent their elimination through phagocytosis. Cancer cells, including leukemic cells, express higher levels of CD47 as a mechanism of protection against macrophage phagocytosis. CD47 blockade leads to an increase in phagocytosis of leukemic cells and better control of the disease. In this review, we explore CD47 function in normal conditions, its role in acute myeloid leukemia progression, and possible ways to block CD47 to enhance elimination of the leukemic cells improving the therapeutic options for patients with acute myeloid leukemia.CD47 is a surface membrane protein expressed by all normal tissues. It is the so-called “don’t eat me signal” because it protects the cells against phagocytosis. The CD47 interacts with the signal regulatory protein alpha (SIRPα) on the surface of macrophages, leading to downstream inhibitory signaling that dampens phagocytic capacity. Since macrophages exert immune surveillance against cancers, cancer cells overexpress CD47 to defend themselves against phagocytosis. Acute myeloid leukemia (AML) is a cancer of hematopoietic stem/progenitor cells (HSPC), and similar to other types of cancers, leukemic blasts show enhanced levels of CD47. In patients with AML, CD47 has been associated with a higher disease burden and poor overall survival. Blockage of CD47-SIRPα signaling leads to improved phagocytosis of AML cells and better overall survival in xenograft models. However, the introduction of a pro-phagocytic signal is needed to induce greater phagocytic capacity. These pro-phagocytic signals can be either Fc receptor stimulants (such as monoclonal antibodies) or natural pro-phagocytic molecules (such as calreticulin). Based on these pre-clinical findings, various clinical trials investigating the blockade of CD47-SIRPα interaction have been designed as monotherapy and in combination with other anti-leukemic agents. In this review, we will discuss CD47 biology, highlight its implications for AML pathophysiology, and explore the potential clinical translation of disrupting CD47-SIRPα to treat patients with AML.

Highlights

  • Using a Similar to murine leukemic stem cells (LSCs), human LSCs and progenitors express grading system to determine the level of CD47 expression, nine (5.2%) of these patients higher levels of CD47 when compared to normal controls, including human bone marrow did not express, 130 (76%) had a low or intermediate level, while 32 (18.7%) expressed and cord‐blood CD34+ hematopoietic stem cell (HSC) together with mobilized peripheral blood (PB) HSCs

  • In individuals with high-risk myelodysplastic syndrome (MDS), CD47 expression is elevated compared to low-risk or normal controls [32]. These findings suggest that CD47 overexpression might be a late event in the malignant evolution of acute myeloid leukemia (AML)

  • The CD47 is a widely expressed protein that protects cells against phagocytosis. It interacts with SIRPα on the surface of macrophages leading to an inhibitory signal that dampens phagocytic activity

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Summary

Introduction

CD47 is a transmembrane protein ubiquitously distributed in tissues, including erythrocytes, platelets, and hematopoietic stem cells It is expressed by both normal and malignant cells being initially recognized as an ovarian tumor protein [1]. CD47-SIRPα interaction on the surface of macrophages results in the intracellular activation of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and phosphorylation of src homology 2 domain-containing phosphatases (SHP-1 and SHP-2), leading to diminished interaction between actin and myosin- 2 [5]. This cascade of events culminates in the inhibition of phagocytosis. We will explore the implications of the CD47-SIRPα axis in AML pathophysiology, highlighting the novel therapeutic opportunities that exploit the blockage of this “don’t eat me” checkpoint

CD47 Structure and Its Ligands
Role of CD47 asinteraction a Phagocytosis
Role of CD47 as a Phagocytosis
Impact of CD47 Expression in AML Prognosis
How Anti-CD47 Therapies Improve Phagocytosis
Results
A Humanized
TTI-621: A SIRPα-IgG1 Fusion Protein
CC-90002
Conclusions
Full Text
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