The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.

التفاصيل البيبلوغرافية
العنوان:	The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.
المؤلفون:	López-Gil JC; Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain.; Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.; Department of Biochemistry, Autónoma University of Madrid (UAM), Madrid, Spain., García-Silva S; Microenvironment and Metastasis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain bsainz@iib.uam.es sgsilva@cnio.es christopher.heeschen@icloud.com., Ruiz-Cañas L; Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain.; Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.; Biobanco Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Navarro D; Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain.; Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.; Department of Biochemistry, Autónoma University of Madrid (UAM), Madrid, Spain., Palencia-Campos A; Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain.; Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Giráldez-Trujillo A; Grupo de Oncología Cutánea, Servicio de Anatomía Patológica, Hospiral Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain., Earl J; Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.; Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain., Dorado J; Stem Cells and Cancer Group, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Gómez-López G; Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Monfort-Vengut A; Cell Cycle and Cancer Biomarkers Laboratory, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain., Alcalá S; Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain.; Department of Biochemistry, Autónoma University of Madrid (UAM), Madrid, Spain., Gaida MM; Institute of Pathology, JGU-Mainz, University Medical Center Mainz, Mainz, Germany.; TRON, JGU-Mainz, Translational Oncology at the University Medical Center, Mainz, Germany.; Research Center for Immunotherapy, JGU-Mainz, University Medical Center Mainz, Mainz, Germany., García-Mulero S; Department of Pathology and Experimental Therapy, Universidad de Barcelona Facultad de Medicina y Ciencias de La Salud, Barcelona, Spain.; Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell), IDIBELL, Barcelona, Spain., Cabezas-Sáinz P; Department of Zoology, Genetics and Physical Anthropology, Veterinary Faculty, Universidade de Santiago de Compostela, Lugo, Spain., Batres-Ramos S; Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain.; Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Barreto E; Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.; Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain.; School of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Spain., Sánchez-Tomero P; Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain.; Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Vallespinós M; Stem Cells and Cancer Group, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Ambler L; Barts Cancer Institute, Queen Mary University of London, London, UK., Lin ML; Barts Cancer Institute, Queen Mary University of London, London, UK., Aicher A; Precision Immunotherapy, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan., García García de Paredes A; Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.; Gastroenterology and Hepatology, Hospital Universitario Ramon y Cajal, Madrid, Spain., de la Pinta C; Radiation Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain., Sanjuanbenito A; Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain.; Pancreatic and Biliopancreatic Surgery Unit, Hospital Universitario Ramon y Cajal, Madrid, Spain., Ruz-Caracuel I; Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain.; Ramon y Cajal University Hospital Anatomy Pathology Service, Madrid, Spain.; Molecular Pathology of Cancer Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Rodríguez-Garrote M; Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.; Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain.; Medical Oncology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain., Guerra C; Experimental Oncology Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Carrato A; Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain.; Medical Oncology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain., de Cárcer G; Cell Cycle and Cancer Biomarkers Laboratory, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain., Sánchez L; Department of Zoology, Genetics and Physical Anthropology, Veterinary Faculty, Universidade de Santiago de Compostela, Lugo, Spain., Nombela-Arrieta C; Department of Medical Oncology and Hematology, University and University Hospital Zurich, Zürich, Switzerland., Espinet E; Department of Pathology and Experimental Therapy, Universidad de Barcelona Facultad de Medicina y Ciencias de La Salud, Barcelona, Spain.; Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell), IDIBELL, Barcelona, Spain., Sanchez-Arevalo Lobo VJ; Grupo de Oncología Cutánea, Servicio de Anatomía Patológica, Hospiral Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.; Grupo de Oncología Molecular, Instituto de Investigaciones Biosanitarias, Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Spain., Heeschen C; Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute - FPO - IRCCS, Candiolo (TO), Italy bsainz@iib.uam.es sgsilva@cnio.es christopher.heeschen@icloud.com., Sainz B Jr; Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain bsainz@iib.uam.es sgsilva@cnio.es christopher.heeschen@icloud.com.; Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.; Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain.
المصدر:	Gut [Gut] 2024 May 16. Date of Electronic Publication: 2024 May 16.
Publication Model:	Ahead of Print
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: British Medical Assn Country of Publication: England NLM ID: 2985108R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-3288 (Electronic) Linking ISSN: 00175749 NLM ISO Abbreviation: Gut Subsets: MEDLINE
أسماء مطبوعة:	Original Publication: London, British Medical Assn.
مستخلص:	Objective: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. Design: We used the KPC mouse model ( LSL-Kras ^G12D/+ ; LSL-Trp53 ^R172H/+ ; Pdx-1-Cre ) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. Results: Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. Conclusions: This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
فهرسة مساهمة:	Keywords: CANCER IMMUNOBIOLOGY; IMMUNE RESPONSE; PANCREATIC CANCER; STEM CELLS
تواريخ الأحداث:	Date Created: 20240516 Latest Revision: 20240516
رمز التحديث:	20240517
DOI:	10.1136/gutjnl-2023-330995
PMID:	38754953
قاعدة البيانات:	MEDLINE

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تدمد:	1468-3288
DOI:	10.1136/gutjnl-2023-330995