Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRP[alpha] axis and a target for cancer immunotherapy

Cancer cells can evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. Expression of programmed death ligand 1 in tumor microenvironments is a major immune checkpoint for tumor-specific T cell responses as it binds to programmed cell death protein-1 on activated and dysfunctional T cells.sup.1. The activity of myeloid cells such as macrophages and neutrophils is likewise regulated by a balance between stimulatory and inhibitory signals. In particular, cell surface expression of the CD47 protein creates a 'don't eat me' signal on tumor cells by binding to SIRP[alpha] expressed on myeloid cells.sup.2-5. Using a haploid genetic screen, we here identify glutaminyl-peptide cyclotransferase-like protein (QPCTL) as a major component of the CD47-SIRP[alpha] checkpoint. Biochemical analysis demonstrates that QPCTL is critical for pyroglutamate formation on CD47 at the SIRP[alpha] binding site shortly after biosynthesis. Genetic and pharmacological interference with QPCTL activity enhances antibody-dependent cellular phagocytosis and cellular cytotoxicity of tumor cells. Furthermore, interference with QPCTL expression leads to a major increase in neutrophil-mediated killing of tumor cells in vivo. These data identify QPCTL as a novel target to interfere with the CD47 pathway and thereby augment antibody therapy of cancer. QPCTL is a modifier of CD47-SIRP[alpha] binding and its blockade enhances macrophage- and neutrophil-mediated antibody dependent cellular cytotoxicity towards tumor cells.
Author(s): Meike E. W. Logtenberg [sup.1] , J. H. Marco Jansen [sup.2] , Matthijs Raaben [sup.3] , Mireille Toebes [sup.1] , Katka Franke [sup.4] , Arianne M. Brandsma [sup.2] , [...]