Abstract A143: Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and target for immunotherapy

Abstract Cancer cells are able to evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. CD47 serves as a “don't eat me” signal for myeloid cells by binding to the inhibitory receptor signal-regulatory protein alpha (SIRPα). Prior work has provided strong evidence that antibody-based targeting of the CD47 axis can promote tumor control by both innate and adaptive immune cells, and clinical development of CD47 antagonists is ongoing. Using a haploid genetic screen, we identify glutaminyl-peptide cyclotransferase-like (QPCTL) as a regulator of the CD47-SIRPα checkpoint that is critical for pyroglutamate formation on CD47 at the SIRPα binding site. Both genetic and pharmacologic interference with QPCTL activity decrease SIRPα binding to CD47 and enhances antibody-dependenT-cellular phagocytosis and cellular cytotoxicity of tumor cells mediated by macrophages and neutrophils, respectively. Furthermore, interference with QPCTL expression leads to a major increase in tumor cell killing and neutrophil influx by tumor-opsonizing antibodies in vivo. These data provide an avenue for small-molecule inhibition of the CD47 pathway to augment antibody therapy of cancer. Citation Format: Meike Emma Willemijn Logtenberg. Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and target for immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A143.