Tolerating CD47

Abstract

Cluster of differentiation 47 (CD47) occupies the outer membrane of human cells, where it binds to soluble and cell surface receptors on the same and other cells, sculpting their topography and resulting in a pleiotropic receptor-multiligand interaction network. It is a focus of drug development to temper and accentuate CD47-driven immune cell liaisons, although consideration of on-target CD47 effects remain neglected. And yet, a late clinical trial of a CD47-blocking antibody was discontinued, existent trials were restrained, and development of CD47-targeting agents halted by some pharmaceutical companies. At this point, if CD47 can be exploited for clinical advantage remains to be determined. Herein an airing is made of the seemingly conflicting actions of CD47 that reflect its position as a junction connecting receptors and signalling pathways that impact numerous human cell types. Prospects of CD47 boosting and blocking are considered along with potential therapeutic implications for autoimmune diseases and cancer.

Keywords: CD47; SIRPα; TSP1; autoimmunity; cancer; checkpoint inhibitor; immunotherapy.

FIGURE 1

CD47 is omnipresent in normal and tumour cell types, associating with other surface molecules displaying diverse functions, including activation, suppression and cell death. CD47 cis activities may contribute to stabilising the expression of cell receptors in the cell synapse (A), eventually leading to synergising or inhibiting the activity of the different associated receptors in multiple cell types. CD47 molecule expression can increase in cancer (B) and in physiological conditions, but a detailed expression kinetics is poorly defined. The association of CD47 in cis to the depicted molecules has been consistently determined, although EGFR is yet presumptive. VEGFR2, vascular endothelial growth factor receptor 2; EGFR, epidermal growth factor receptor; FAS (human), aka Fas cell surface death receptor, aka tumour necrosis factor receptor superfamily member 6 receptor.

FIGURE 2

TSP1‐CD47‐SIRPα interactome in cancer immunotherapy and the case for type 1 diabetes. The conventional ‘don't eat me signal’ mediated by the forward negative effect in trans of CD47 on macrophages, postulated to be interfered with current blocking antibodies (mAbs). An inclusive ‘Immune triangle’ views the TSP1‐CD47‐SIRPα interactome converging multiple checkpoints, with the SIRPα central immune regulatory role also acting as a multitier protection both in cis and by reverse effect in trans, representing a natural mechanism of homeostasis to maintain peripheral tolerance (A). Absence of SIRPα in human β cells may increase vulnerability to self‐reactivity in genetically predisposed individuals by disrupting innate and adaptive immunity (B). SIRPα inhibitory effect in cis, as well as its reverse effect in trans, is potentially impaired. An on‐target effect of current CD47 immune checkpoint inhibitor mAbs damaging human β‐cell function and impacting T‐cell health should be entertained and elucidated. – indicates inhibitory effect; x inactive due to lack of SIRPα effect in trans and ? indicates unknown effect.