Versatile activatable vSIRPα-probe for cancer-targeted imaging and macrophage-mediated phagocytosis of cancer cells

Abstract

Signal-regulatory protein alpha (SIRPα) engaged by CD47, that is overexpressed in a wide range of human solid tumors, serves as a ‘Don't eat me’ signal for phagocytic cells such as macrophages and dendritic cells. The SIRPα-CD47 interactions have recently attracted increasing attention in both cancer diagnosis and cancer immunotherapy. Herein, we designed and suggested a lysosomal enzyme-activatable vSIRPα-probe (vSIRPα-probe) capable of facilitating CD47-targeted cancer imaging and eliciting anti-cancer immune responses depending on phagocytosis as a versatile platform for potential cancer theranostic applications. For more efficient and precise cancer targeting, a recombinant SIRPα variant (vSIRPα) having a 50,000-fold higher binding affinity to CD47 than wild-type SIRPα was used to fabricate the vSIRPα-probe by conjugating to a dark-quenched fluorogenic peptide that is a substrate of lysosomal endopeptidases. The vSIRPα-probe could specifically bind to CD47 in different types of cancer cells and be activated by dequenching after cellular internalization. By interrupting the SIRPα-CD47 interaction between macrophages and cancer cells, the vSIRPα-probe promoted the destruction of cancer cells by macrophage-mediated phagocytosis, which was highly comparable to the un-modified vSIRPα recombinant protein. In the mouse tumor-xenografts treated with intravenous injection of the vSIRPα-probe, its enhanced in vivo tumor-targeting and imaging abilities drastically diminished after blocking the SIRPα-CD47 interaction via intratumoral administration of anti-CD47 antibodies. This study demonstrates that our vSIRPα-probe provides a promising tumor-targeted immunotheranostic probe for a novel cancer diagnostic and therapeutic strategy.