Using genetic screening and biochemical analysis, Logtenberg et al. found that glutaminyl-peptide cyclotransferase-like protein (QPCTL) plays an enzymatic role in modifying the SIRPα binding site on CD47 (the “don’t eat me” signal) shortly after the CD47 protein is synthesized. Genetically knocking out QPCTL in tumor cells or using small molecule inhibitors of QPCTL interfered with the CD47-SIRPα axis, enhancing antibody-dependent, neutrophil-mediated tumor cell killing and macrophage-mediated phagocytosis of tumor cells. Targeting QPCTL to interfere with the CD47 pathway could be a novel strategy for 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(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 SIRPalpha expressed on myeloid cells(2-5). Using a haploid genetic screen, we here identify glutaminyl-peptide cyclotransferase-like protein (QPCTL) as a major component of the CD47-SIRPalpha checkpoint. Biochemical analysis demonstrates that QPCTL is critical for pyroglutamate formation on CD47 at the SIRPalpha 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.
Author Info: (1) Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (2) Laboratory for Translational Immunology, UMC
Author Info: (1) Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (2) Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (3) Division of Biochemistry, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (4) Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (5) Department of Blood Cell Research, Sanquin Research, Landsteiner Laboratory, and Department of Molecular Cell Biology, Amsterdam University Medical Center, Amsterdam, The Netherlands. (6) Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (7) Department of Blood Cell Research, Sanquin Research, Landsteiner Laboratory, and Department of Molecular Cell Biology, Amsterdam University Medical Center, Amsterdam, The Netherlands. (8) Division of Biochemistry, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (9) Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (10) Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (11) Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (12) Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (13) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. Institute for Chemical Immunology, Amsterdam, The Netherlands. (14) Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (15) Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (16) Institute for Chemical Immunology, Amsterdam, The Netherlands. Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (17) Department of Blood Cell Research, Sanquin Research, Landsteiner Laboratory, and Department of Molecular Cell Biology, Amsterdam University Medical Center, Amsterdam, The Netherlands. (18) Division of Biochemistry, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (19) Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (20) Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (21) Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. t.schumacher@nki.nl. Institute for Chemical Immunology, Amsterdam, The Netherlands. t.schumacher@nki.nl.
