ReviewBlocking “don't eat me” signal of CD47-SIRPα in hematological malignancies, an in-depth review
Introduction
Cluster of Differentiation 47 (CD47) is a heavily glycosylated, ubiquitously expressed cell surface protein in the immunoglobulin superfamily that has characterized roles in important cellular functions like proliferation, adhesion, migration, apoptosis and phagocytosis. Its molecular structure includes an extracellular immunoglobulin variable (IgV)-like domain, a transmembrane spanning domain, and a short, alternatively spliced cytoplasmic tail [1]. CD47 has been shown to interact in cis with integrins, and in trans with both thrombospondin (TSP-1) and signal regulatory protein alpha (SIRPα) [2] [3]. Research shows that it mediates vascular smooth cell proliferation and migration [4], platelet activation and spreading [5], and recruitment of granulocytes and T cells to sites of infection [6,7].
Apoptosis or programmed cell death (PCD) is a physiologically important mechanism for maintaining homeostasis. It can be divided into type I, type II and type III PCD; the first two are caspase dependent and type III is caspase-independent [8]. CD47 also functions as a marker of “self” on host cells within an organism. When expressed, CD47 binds to SIRPα on the surface of circulating immune cells to deliver an inhibitory “don't eat me” signal [9]. SIRPα encodes an Ig-superfamily receptor expressed on the surface of macrophages and dendritic cells, whose cytoplasmic region contains immunoreceptor tyrosine-based inhibition motifs (ITIMs) that can trigger a cascade to inhibit phagocytosis. CD47-SIRPα binding results in phosphorylation of ITIMs on SIRPα, which triggers recruitment of Src homology phosphatases, SHP1 and SHP2. These phosphatases can in turn inhibit accumulation of myosin II at the phagocytic synapse, preventing phagocytosis [10].
Phagocytosis of target cells by macrophages is ultimately regulated by a balance of activating signals (FcγR, CRT, LRP-1) and inhibitory signals (SIRPα-CD47) (Reviewed in [11]). This balance is tipped by cancer cells, which co-opt the “self” signal and upregulate CD47 expression to evade immune surveillance and subsequent destruction. Elevated expression of CD47 has been observed in ovarian carcinoma cell lines [12,13], murine myeloid leukemias [14], leukemic stem cells [14,15] and several solid tumors [16].
Specifically, CD47 expression of human acute lymphoblastic leukemia (ALL) samples was measured as two-fold increased compared to normal bone marrow samples and expression level was predictive of survival and refractoriness to primary treatment in pediatric populations [17]. Flow cytometry revealed high surface expression of CD47 on 73% of samples collected from the bone marrow of multiple myeloma (MM) patients [18]. These results corroborate earlier findings by microarray analysis [19] and were also mirrored in high CD47 expression of several MM cell lines [18]. Goto et al. revealed high CD47 expression on six different primary effusion lymphoma (PEL) cell lines compared to peripheral blood mononuclear cells (PBMC) [20]. Additionally, in acute myeloid leukemia (AML), ALL, and several non-Hodgkin's lymphoma (NHL) subtypes, increased CD47 expression is correlated with adverse clinical outcomes [15,16,21].
Hematological malignancies, even at onset, present with widespread bone marrow and peripheral blood involvement and many are still without effective systemic curative therapies [22]. Several anti-CD47 antibodies have been studied in vitro and in vivo with promising results using cell lines and mouse models of hematological malignancy. From this body of research, three different mechanisms of action of anti-CD47 antibodies have been proposed including: initiation of type III PCD of tumor cells, blockade of tumor cell anti-phagocytic signaling, and stimulation of cytotoxic T cell priming against tumor cells. Thus far, it is understood that CD47 blockade on normal cells does not trigger phagocytosis without a pro-phagocytic stress signal, such as calreticulin or phosphatidylserine, which induces phagocytosis by binding to its receptor, low density lipoprotein-receptor related protein (LRP), on phagocytic cells [23,24]. In addition to interfering with CD47/SIRPα interactions, function-blocking CD47 antibodies may target cancer stem cells [25,26] and enhance tumor sensitivity to radiation therapy while providing protection to normal tissue [27,28]. The goal of this review is to provide a systematic and comprehensive overview of the published preclinical data to support the use of anti-CD47 antibody therapies in clinical trials to treat hematological malignancies.
Section snippets
Methods
To perform a comprehensive survey of the available preclinical literature on anti-CD47 antibody treatment in hematological malignancies, we searched literature using key words: “CD47” OR “CD47 antibody” OR “anti-CD47” AND “Lymphoma” OR “Leukemia” OR “hematological malignancy” OR “Hematological malignancies”. A systematic literature search was performed using the databases: PubMed, Embase, SCOPUS, Web of Science, identifying a total of 521 records (Table 1). References from all identified
Leukemia
Early studies on the efficacy of anti-CD47 antibodies proposed that malignant cells were eliminated via type III PCD. Mateo et al. utilized the first anti-CD47 antibody in an in-vitro B cell chronic lymphocytic leukemia (B-CLL) model and showed that the induction of caspase-independent PCD in B-CLL by CD47 ligation using an unspecified anti-CD47 monoclonal antibody was not inhibited by a broad-spectrum caspase inhibitor (zVAD-fmk) or the presence of exogenous rescuing cytokines (IL-4 or
Discussion
There is a large body of preclinical evidence and emerging clinical data supporting the use of anti-CD47 antibodies in several hematological malignancies both as a monotherapy and as a combination strategy (Table 3). In hematological cancers, where tumor cells express high levels of CD47 as a mechanism of immune evasion, antibodies designed to block the SIRPα-CD47 interaction offer a compelling therapeutic strategy to prevent escape and promote innate and adaptive immune system clearance of
Practice points
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A large body of preclinical evidence and emerging clinical data supports the use of anti-CD47 antibodies in several hematological malignancies both as a monotherapy and as a combination strategy.
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Anti-cancer effects of CD47-SIRPα are exerted via phagocytosis and cytotoxic T cell priming.
Research agenda
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Improved standard protocol for treating hematological malignancies with additional Phase I testing using antibody molecules designed to target the CD47-SIRPα interaction.
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Evaluation of testing in combination with immune-inhibitor and immune-modulators.
Conflict of interest
Atlantis Russ MD, PhD, Anh B. Hua BS, William R. Montfort PhD, Bushra Rahman MS, MD, Irbaz Bin Riaz MS, MD, Muhammad Umar Khalid MD, Jennifer S. Carew PhD, Steffan T. Nawrocki PhD, Daniel Persky MD, and Faiz Anwer MD, FACP report nothing to declare as conflict regarding this publication.
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Atlantis Russ and Anh Hua share the first co-authorship.