Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47

Abstract

Introduction: CD47 is a ubiquitously expressed cell surface receptor that serves as a counter-receptor for SIRPα in recognition of self by the innate immune system. Independently, CD47 also functions as an important signaling receptor for regulating cell responses to stress.

Areas covered: We review the expression, molecular interactions, and pathophysiological functions of CD47 in the cardiovascular and immune systems. CD47 was first identified as a potential tumor marker, and we examine recent evidence that its dysregulation contributes to cancer progression and evasion of anti-tumor immunity. We further discuss therapeutic strategies for enhancing or inhibiting CD47 signaling and applications of such agents in preclinical models of ischemia and ischemia/reperfusion injuries, organ transplantation, pulmonary hypertension, radioprotection, and cancer.

Expert opinion: Ongoing studies are revealing a central role of CD47 for conveying signals from the extracellular microenvironment that limit cell and tissue survival upon exposure to various types of stress. Based on this key function, therapeutics targeting CD47 or its ligands thrombospondin-1 and SIRPα could have broad applications spanning reconstructive surgery, engineering of tissues and biocompatible surfaces, vascular diseases, diabetes, organ transplantation, radiation injuries, inflammatory diseases, and cancer.

Fig. 1. CD47 interacting partners

On most cell types CD47 laterally associates with β3 integrins and certain β1 integrins. RBC lack integrins, and CD47 instead associates with the Rh antigen complex, which links CD47 to the cytoskeleton via ankyrin and spectrin. Additional cell type-specific lateral interactions of CD47 have been identified involving SIRPα, VEGFR2, and the Fas receptor. Cytoplasmic binding partners include PLIC1, which in turn binds to Gβγ, and BNIP3.

Fig. 2. CD47 signal transduction

Engagement of CD47 by TSP1 inhibits its lateral interaction with VEGFR2 and modulates signaling mediated by Ca²⁺, cGMP, and cAMP in vascular cells. CD47 ligation also controls cell survival via mitochondrial dependent pathways mediated by translocation of BNIP3 and suppression of a protective autophagy pathway that blocks apoptosis. CD47 also serves as the counter-receptor for SIRPα. Engagement of SIRPα on phagocytic cells suppresses phagocytic killing of target cells.

Fig. 3. Therapeutic strategies to target CD47

Therapeutic effects have been reported using TSP1 antibodies that selectively inhibit TSP1/CD47 signaling and using soluble recombinant extracellular domains of CD47 and SIRPα, which act as decoys to selectively block inhibitory signaling through SIRPα. CD47 blocking antibodies such as B6H12 inhibit both TSP1 and SIRPα binding. Antisense suppression of CD47 expression using morpholinos similarly provides global inhibition of CD47 functions. More selective inhibition TSP1/CD47 versus CD47/SIRPα signaling may be achievable using small molecules or peptides designed to inhibit each CD47 interaction.