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Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and a target for cancer immunotherapy.

التفاصيل البيبلوغرافية
العنوان: Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and a target for cancer immunotherapy.
المؤلفون: Logtenberg MEW; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Jansen JHM; Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands., Raaben M; Division of Biochemistry, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Toebes M; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Franke K; Department of Blood Cell Research, Sanquin Research, Landsteiner Laboratory, and Department of Molecular Cell Biology, Amsterdam University Medical Center, Amsterdam, The Netherlands., Brandsma AM; Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands., Matlung HL; Department of Blood Cell Research, Sanquin Research, Landsteiner Laboratory, and Department of Molecular Cell Biology, Amsterdam University Medical Center, Amsterdam, The Netherlands., Fauster A; Division of Biochemistry, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Gomez-Eerland R; Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Bakker NAM; Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., van der Schot S; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Marijt KA; Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands., Verdoes M; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.; Institute for Chemical Immunology, Amsterdam, The Netherlands., Haanen JBAG; Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., van den Berg JH; Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Neefjes J; Institute for Chemical Immunology, Amsterdam, The Netherlands.; Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., van den Berg TK; Department of Blood Cell Research, Sanquin Research, Landsteiner Laboratory, and Department of Molecular Cell Biology, Amsterdam University Medical Center, Amsterdam, The Netherlands., Brummelkamp TR; Division of Biochemistry, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Leusen JHW; Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands., Scheeren FA; Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands., Schumacher TN; 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.
المصدر: Nature medicine [Nat Med] 2019 Apr; Vol. 25 (4), pp. 612-619. Date of Electronic Publication: 2019 Mar 04.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE
أسماء مطبوعة: Publication: New York Ny : Nature Publishing Company
Original Publication: New York, NY : Nature Pub. Co., [1995-
مواضيع طبية MeSH: Immunotherapy*, Aminoacyltransferases/*metabolism , Antigens, Differentiation/*metabolism , CD47 Antigen/*metabolism , Neoplasms/*immunology , Neoplasms/*therapy , Receptors, Immunologic/*metabolism, Aminoacyltransferases/antagonists & inhibitors ; Animals ; Cell Line, Tumor ; Cell Membrane/metabolism ; Humans ; Mice, Transgenic ; Neoplasms/pathology ; Opsonin Proteins/metabolism ; Pyrrolidonecarboxylic Acid/metabolism
مستخلص: 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 SIRPα 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-SIRPα checkpoint. Biochemical analysis demonstrates that QPCTL is critical for pyroglutamate formation on CD47 at the SIRPα 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.
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معلومات مُعتمدة: 742259 International ERC_ European Research Council
المشرفين على المادة: 0 (Antigens, Differentiation)
0 (CD47 Antigen)
0 (Opsonin Proteins)
0 (Receptors, Immunologic)
0 (SIRPA protein, human)
EC 2.3.2.- (Aminoacyltransferases)
EC 2.3.2.5 (glutaminyl-peptide cyclotransferase)
SZB83O1W42 (Pyrrolidonecarboxylic Acid)
تواريخ الأحداث: Date Created: 20190306 Date Completed: 20190510 Latest Revision: 20220218
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC7025889
DOI: 10.1038/s41591-019-0356-z
PMID: 30833751
قاعدة البيانات: MEDLINE
الوصف
تدمد:1546-170X
DOI:10.1038/s41591-019-0356-z