SIRPα controls CD47-dependent platelet clearance in mice and humans

Abstract

Over the last decade, more data has revealed that increased surface expression of the "dont eat me" CD47 protein on cancer cells plays a role in immune evasion and tumor progression, with CD47 blockade emerging as a new therapy in immuno-oncology. CD47 is critical in regulating cell homeostasis and clearance, as binding of CD47 to the inhibitory receptor SIRP can prevent phagocytosis and macrophage-mediated cell clearance. The purpose of this study was to examine the role of the CD47-SIRP signal in platelet homeostasis and clearance. Therapeutic reagents targeting the CD47-SIRP axis are very promising for treatment of hematologic malignancies and solid tumors, but lead to transient anemia or thrombocytopenia in a subset of patients. We found that platelet homeostatic clearance is regulated through the CD47-SIRP axis and that therapeutic blockade to disrupt this interaction in mice and in humans has a significant impact on platelet levels. Furthermore, we identified genetic variations at the SIRPA locus that impact platelet levels in humans such that higher SIRPA gene expression is associated with higher platelet levels. SIRPA expression at either end of the normal range may affect clinical outcomes of treatment with anti-CD47 therapy. Key pointsO_LIPlatelet homeostasis is regulated through the CD47-SIRP axis and therapeutic blockade to disrupt this interaction impacts platelet levels C_LIO_LICommon genetic variants at SIRPA locus associate with platelet levels C_LI