Multimodal single-cell profiling reveals crosstalk between macrophages and stromal cells in poor prognostic cholangiocarcinoma patients
npj Precision Oncology, vol. 10
Abstract
Abstract Background and aims Cholangiocarcinoma (CCA) is a deadly disease, and this cancer entity is characterized by an abundant stroma. The tumor microenvironment (TME) plays an important role in aggressive behavior and poor response to therapeutics; however, underlying pathways are unknown. Methods To fill this gap, we used multiplexed immunohistochemistry, high-dimensional phenotyping, and transcriptomics to analyze human CCA samples and identify cell cluster crosstalk in patients with a poor prognosis. Results Our findings confirmed the presence of Tregs and the lack of effector memory cells in the tumor. New findings are the spatiality of the effector memory cells being more present in the peripheral tissue, for some reason these immune cells fail to reach the tumor niche. We revealed cancer crosstalk with macrophages and stromal cells and identified responsible genes in the poor prognosis group. Amongst the responsible ligand pairs are GAS6-AXL belonging to the TAM family. We then identified VCAN-TLR2 to be present and influencing the ECM in a way to supports immune exhaustion. Last, EGFR-TGF-β is expressed in macrophages and this finding is important in Tregs induction and blocking cytotoxic T cell function. Conclusions The multiple mechanisms leading to the exclusion of relevant immune cells needed for an anti-cancer response and mechanisms leading to active immune suppression are part of complex cell-cell crosstalk. This study provides a deeper insight into the immune exhausted phenotype in CCA.
Authors 33
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Lara Heij corresponding Aachen Department of Renal and Hypertensive Disorders Rheumatological and Immunological Diseases (Medical Clinic II) Medical Faculty
Erasmus MC · Essen University Hospital · RWTH Aachen University
Affiliation as printed
Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Roterdam, The Netherlands. lararosaline.heij@uk-essen.de
Department of Pathology, University Hospital Essen, Essen, Germany. lararosaline.heij@uk-essen.de
Department of Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases (Medical Clinic II), Medical Faculty, RWTH Aachen University, Aachen, Germany. lararosaline.heij@uk-essen.de
Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany. lararosaline.heij@uk-essen.de
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Sikander Hayat Aachen Department of Renal and Hypertensive Disorders Rheumatological and Immunological Diseases (Medical Clinic II) Medical Faculty
RWTH Aachen University · Icahn School of Medicine at Mount Sinai
Affiliation as printed
Cardiovascular Research Institute and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
Department of Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases (Medical Clinic II), Medical Faculty, RWTH Aachen University, Aachen, Germany
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Maastricht University · Essen University Hospital · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam UMC - Location Vrije Universiteit Amsterdam, Molecular Cell Biology & Immunology, Amsterdam, The Netherlands
Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany
NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
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Sidrah Maryam Aachen Department of Renal and Hypertensive Disorders Rheumatological and Immunological Diseases (Medical Clinic II) Medical Faculty
Affiliation as printed
Department of Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases (Medical Clinic II), Medical Faculty, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Health and Medical Sciences, Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
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Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Infection & Immunity, Cancer Immunology, Amsterdam, The Netherlands
Amsterdam UMC - Location Vrije Universiteit Amsterdam, Molecular Cell Biology & Immunology, Amsterdam, The Netherlands
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Amsterdam University Medical Centers · University of Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Infection & Immunity, Cancer Immunology, Amsterdam, The Netherlands
Amsterdam UMC - Location Vrije Universiteit Amsterdam, Molecular Cell Biology & Immunology, Amsterdam, The Netherlands
Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
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Maurice Halder Aachen Department of Renal and Hypertensive Disorders Rheumatological and Immunological Diseases (Medical Clinic II) Medical Faculty
Affiliation as printed
Department of Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases (Medical Clinic II), Medical Faculty, RWTH Aachen University, Aachen, Germany
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Fabian Peisker Aachen Department of Renal and Hypertensive Disorders Rheumatological and Immunological Diseases (Medical Clinic II) Medical Faculty
Affiliation as printed
Department of Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases (Medical Clinic II), Medical Faculty, RWTH Aachen University, Aachen, Germany
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Maastricht University Medical Centre · Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
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Affiliation as printed
Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany
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Affiliation as printed
Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
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Affiliation as printed
Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany
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Affiliation as printed
Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany
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Düsseldorf University Hospital
Affiliation as printed
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Düsseldorf, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany
Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
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Medizinische Hochschule Hannover · Universitätsklinikum Aachen · German Center for Lung Research · RWTH Aachen University
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany
Institute of Pathology, Hannover Medical School, Hannover, Germany
Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
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Affiliation as printed
Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany
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University Hospitals Birmingham NHS Foundation Trust · University of Birmingham
Affiliation as printed
University of Birmingham and University hospitals of Birmingham NHS Trust, Birmingham, UK
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Essen University Hospital · University of Duisburg-Essen
Affiliation as printed
Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
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Oregon Health & Science University · OHSU Knight Cancer Institute
Affiliation as printed
Division of Surgical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
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Affiliation as printed
Department of Pathology, University Hospital Essen, Essen, Germany
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Affiliation as printed
Department of Pathology, University Hospital Essen, Essen, Germany
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Affiliation as printed
Department of Health and Medical Sciences, Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
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TU Dortmund University · Leibniz Research Centre for Working Environment and Human Factors
Affiliation as printed
Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany
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South Valley University · TU Dortmund University · Leibniz Research Centre for Working Environment and Human Factors
Affiliation as printed
Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany
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TU Dortmund University · Leibniz Research Centre for Working Environment and Human Factors
Affiliation as printed
Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany
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Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Infection & Immunity, Cancer Immunology, Amsterdam, The Netherlands
Amsterdam UMC - Location Vrije Universiteit Amsterdam, Molecular Cell Biology & Immunology, Amsterdam, The Netherlands
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Rafael Kramann Aachen Department of Renal and Hypertensive Disorders Rheumatological and Immunological Diseases (Medical Clinic II) Medical Faculty
Affiliation as printed
Department of Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases (Medical Clinic II), Medical Faculty, RWTH Aachen University, Aachen, Germany
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Maastricht University Medical Centre · Maastricht University · Essen University Hospital
Affiliation as printed
Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany
Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
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