CD47: a valid target for anti-cancer stem cell therapy

Cluster Differentiation 47 (CD47), an immune checkpoint protein, is a type I, five-pass transmembrane protein with an extracellular IgV domain and a short cytoplasmic tail. CD47 plays essential roles in tissue homeostasis and remodeling, including aged red blood cell removal, platelet turnover, circulating hematopoietic stem cell turnover, and brain synaptic plasticity. CD47 is expressed in most tissues except for with low expression in pancreas.

Surface expressed CD47 can suppress the ?Eat me? signals (opsonizing IgG, complement, and calreticulin) conveyed from aberrant cells to surveying myeloid cells (e.g., macrophages, neutrophils), when it is recognized by Signal-regulatory protein alpha (SIRP?) on those phagocytic cells. The downstream signaling of SIRP? after ligation of CD47 is not clear. It might include relocation of SIRP? to Src-kinase rich phagocytic synapse, phosphorylation at its cytoplasmic ITIM/ITSM (immunoreceptor tyrosine-based inhibitory/switch motif), inhibition of inside-out activation of integrins, and recruitment of tyrosine phosphatases (SHP-1 and SHP-2). The IgV domain of CD47 can also bind to integrins in cis or thrombospondin-1 (THBS1) to modulate cell-cell or cell-matrix interactions.

Blockade of CD47 (e.g., function-blocking anti-CD47 antibodies) can lead to phagocytosis of the pathogenic cells. This approach is reported to improve the condition of some inflammation related diseases, including vascular inflammation, atherosclerosis, and fibrosis. In addition, like other found immune checkpoint pathways (i.e., PD-L1/PD-1, MHC I/ LILRB1, and CD24/Siglec-10), suppression of CD47/SIRP? axis, has also been reported as an effective treatment when combined with various molecular targeted cancer therapies.

Tools for analyzing the CD47-SIRP? Axis and related pathways

CD47-SIRP? Axis

CD47 | SIRPA | LYN | LCK | HCK | PTPN6 | PTPN11

CD47 Binding Protein

THBS1 | ITGA2 | ITGA2B | ITGAV | ITGB1 | ITGB3

Other Immune Checkpoint Protein

PDCD1 | CD274 | LILRB1 | CD24 | SIGLEC10

References:

• Logtenberg et al. 2020 May 19;52(5):742-752. doi: 10.1016/j.immuni.2020.04.011
• Morrissey et al. 2020 Aug 18;53(2):290-302.e6. doi: 10.1016/j.immuni.2020.07.008
• Kojima et al. 2016 Aug 4;536(7614):86-90. doi: 10.1038/nature18935
• Jarr et al. 2021 Jan 28;384(4):382-383. doi: 10.1056/NEJMc2029834