CD47 Is Upregulated on Circulating Hematopoietic Stem Cells and Leukemia Cells to Avoid Phagocytosis

Abstract

Summary Macrophages clear pathogens and damaged or aged cells from the blood stream via phagocytosis. Cell-surface CD47 interacts with its receptor on macrophages, SIRPα, to inhibit phagocytosis of normal, healthy cells. We find that mobilizing cytokines and inflammatory stimuli cause CD47 to be transiently up-regulated on mouse hematopoietic stem cells (HSCs) and progenitors just prior to and during their migratory phase, and that the level of CD47 on these cells determines the probability that they are engulfed in vivo. CD47 is also constitutively up-regulated on mouse and human myeloid leukemias and over-expression of CD47 on a myeloid leukemia line increases its pathogenicity by allowing it to evade phagocytosis. We conclude that CD47 up-regulation is an important mechanism that provides protection to normal HSCs during inflammation-mediated mobilization, and that leukemic progenitors co-opt this ability in order to evade macrophage killing.

Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells

“…However, when bone marrow HSCs were mobilized out of bone marrow, they upregulated CD47. 11 Ide et al 30 demonstrated that the overexpression of CD47 on donor cells or treatment of recipient mice with soluble CD47 enhanced the engraftment of xenogenic donor cells. This suggests that the overexpression of CD47 may be correlated with higher resistance to phagocytosis by macrophages.…”

“…Anti-CD47 monoclonal antibodies inhibiting the interaction of CD47 and SIRPa promote the phagocytosis of tumor cells by macrophages, and also by monocytes and neutrophils. [9][10][11] Cancer cells including acute myelogenous leukemias, 11,12 lymphomas, 13,14 and various solid cancers [15][16][17] express CD47 at a high level, and can be phagocytosed by macrophages in the presence of blocking antibodies to CD47. [11][12][13][14][15][16][17] In those cases where the tumor-initiating cells (or cancer stem cells) are known, for example, from acute myelogenous leukemias and bladder cancers, the tumor-initiating cells also upregulate CD47 expression, possibly to avoid phagocytosis.…”

How One Thing Led to Another

“…We realized that our AML LSC gene encoded a protein that is a "don't eat me" signal (226). We rapidly showed that CD47-negative HSCs cannot engraft in wild-type irradiated hosts (224). We found that normal HSCs mobilized by Cytoxan and G-CSF upregulated CD47 transiently, then extravasated into the bloodstream (224), whereupon they homed rapidly to the vascular sinusoids of bone marrow, spleen, and liver (224), presumably using integrin α 4 β 1 to bind luminal VCAM1, then followed their cell surface chemokine receptor CXCR4 and transmigrated across fields of perivascular sinusoidal macrophages to reach CXCL12-secreting niches (227)(228)(229)(230)(231).…”

“…We found that normal HSCs mobilized by Cytoxan and G-CSF upregulated CD47 transiently, then extravasated into the bloodstream (224), whereupon they homed rapidly to the vascular sinusoids of bone marrow, spleen, and liver (224), presumably using integrin α 4 β 1 to bind luminal VCAM1, then followed their cell surface chemokine receptor CXCR4 and transmigrated across fields of perivascular sinusoidal macrophages to reach CXCL12-secreting niches (227)(228)(229)(230)(231). Knockdown of leukemia cell CD47 led to their elimination by macrophages in vitro, and upon intravenous injection in vivo, they were removed by sinusoidal tissue macrophages (224). CD47-negative cell lines placed in vitro with macrophages usually are phagocytosed, whereas the same cells transfected with and expressing CD47 were not (224).…”

Monocytes and Macrophages in Cancer: Development and Functions

“…Tumor cells were shown to constitutively up-regulate CD47 expression in multiple tumor entities and animal models. Furthermore, over-expression of CD47 was a poor prognostic factor and correlated with increased pathogenicity [106][107][108][109][110]. Treatment of solid or hematopoietic tumors with either CD47-specific blocking antibodies or SIRPα-fusion proteins resulted in an increase in macrophage-dependent phagocytosis of tumor cells and a corresponding decrease in tumor size and number of metastases [107][108][109][110][111].…”