Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment.

Adenocarcinoma / drug therapy Carcinoma, Pancreatic Ductal / drug therapy Humans Immune Checkpoint Inhibitors Pancreatic Neoplasms / drug therapy Tumor Microenvironment

Journal

Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119

Informations de publication

Date de publication:
03 2022
Historique:
received: 05 12 2020
accepted: 13 12 2021
pubmed: 6 2 2022
medline: 5 4 2022
entrez: 5 2 2022
Statut: ppublish

Résumé

KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted and immunotherapies. Among the different PDAC subtypes, basal-like mesenchymal PDAC, which is driven by allelic imbalance, increased gene dosage and subsequent high expression levels of oncogenic KRAS, shows the most aggressive phenotype and strongest therapy resistance. In the present study, we performed a systematic high-throughput combination drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib, which targets KRAS-directed oncogenic signaling in mesenchymal PDAC. This combination treatment induces cell-cycle arrest and cell death, and initiates a context-dependent remodeling of the immunosuppressive cancer cell secretome. Using a combination of single-cell RNA-sequencing, CRISPR screens and immunophenotyping, we show that this combination therapy promotes intratumor infiltration of cytotoxic and effector T cells, which sensitizes mesenchymal PDAC to PD-L1 immune checkpoint inhibition. Overall, our results open new avenues to target this aggressive and therapy-refractory mesenchymal PDAC subtype.

Identifiants

DOI: 10.1038/s43018-021-00326-1 PMID: 35122074 PMC: PMC7612546
pubmed: 35122074
doi: 10.1038/s43018-021-00326-1
pii: 10.1038/s43018-021-00326-1
pmc: PMC7612546
mid: EMS140566
doi:

Substances chimiques

Immune Checkpoint Inhibitors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

318-336

Subventions

Organisme : European Research Council
ID : 648521
Pays : International

Informations de copyright

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

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Auteurs

Chiara Falcomatà (C)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.

Stefanie Bärthel (S)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
ORCID: 0000-0001-5986-4864

Sebastian A Widholz (SA)

Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany.
German Cancer Consortium, Heidelberg, Germany.
ORCID: 0000-0002-4566-2986

Christian Schneeweis (C)

German Cancer Consortium, Heidelberg, Germany.
Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Juan José Montero (JJ)

Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany.
German Cancer Consortium, Heidelberg, Germany.

Albulena Toska (A)

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.
ORCID: 0000-0002-4519-9493

Jonas Mir (J)

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.
ORCID: 0000-0003-2067-6289

Thorsten Kaltenbacher (T)

Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany.
German Cancer Consortium, Heidelberg, Germany.
ORCID: 0000-0001-8233-4749

Jeannine Heetmeyer (J)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.

Jonathan J Swietlik (JJ)

Experimental Systems Immunology Laboratory, Max Planck Institute of Biochemistry, Martinsried, Germany.

Jing-Yuan Cheng (JY)

Experimental Systems Immunology Laboratory, Max Planck Institute of Biochemistry, Martinsried, Germany.
ORCID: 0000-0001-8942-0607

Bianca Teodorescu (B)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.

Oliver Reichert (O)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.

Constantin Schmitt (C)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.

Kathrin Grabichler (K)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.

Andrea Coluccio (A)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Fabio Boniolo (F)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.

Christian Veltkamp (C)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.

Magdalena Zukowska (M)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.

Angelica Arenas Vargas (AA)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.

Woo Hyun Paik (WH)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
ORCID: 0000-0001-8708-3280

Moritz Jesinghaus (M)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
Institute of Pathology, Technische Universität München, Munich, Germany.
Institute of Pathology, University Hospital Marburg, Marburg, Germany.
ORCID: 0000-0002-0018-5661

Katja Steiger (K)

Institute of Pathology, Technische Universität München, Munich, Germany.
ORCID: 0000-0002-7269-5433

Roman Maresch (R)

Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany.
German Cancer Consortium, Heidelberg, Germany.

Rupert Öllinger (R)

Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany.
German Cancer Consortium, Heidelberg, Germany.

Tim Ammon (T)

Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
German Cancer Consortium, Heidelberg, Germany.
Institute of Experimental Hematology, School of Medicine, Technical University of Munich, Munich, Germany.

Olga Baranov (O)

Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany.
German Cancer Consortium, Heidelberg, Germany.

Maria S Robles (MS)

Institute of Medical Psychology, Faculty of Medicine, LMU Munich, Munich, Germany.

Julia Rechenberger (J)

Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany.

Bernhard Kuster (B)

German Cancer Consortium, Heidelberg, Germany.
Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany.
ORCID: 0000-0002-9094-1677

Felix Meissner (F)

Experimental Systems Immunology Laboratory, Max Planck Institute of Biochemistry, Martinsried, Germany.
Institute of Innate Immunity, Department of Systems Immunology and Proteomics, Medical Faculty, University of Bonn, Bonn, Germany.

Maximilian Reichert (M)

German Cancer Consortium, Heidelberg, Germany.
Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Center for Protein Assemblies, Technische Universität München, Garching, Germany.

Michael Flossdorf (M)

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.

Roland Rad (R)

Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany.
German Cancer Consortium, Heidelberg, Germany.
Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
ORCID: 0000-0002-6849-9659

Marc Schmidt-Supprian (M)

Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
German Cancer Consortium, Heidelberg, Germany.
Institute of Experimental Hematology, School of Medicine, Technical University of Munich, Munich, Germany.

Günter Schneider (G)

German Cancer Consortium, Heidelberg, Germany.
Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
University Medical Center Göttingen, Department of General, Visceral and Pediatric Surgery, Göttingen, Germany.
ORCID: 0000-0003-1840-4508

Dieter Saur (D)

Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany. dieter.saur@tum.de.
Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany. dieter.saur@tum.de.
Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany. dieter.saur@tum.de.
Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. dieter.saur@tum.de.
ORCID: 0000-0001-5874-0210

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Classifications MeSH

questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › Selective multi-kinase inhibition sensitizes...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Carcinome du canal pancréatique › Selective multi-kinase inhibition sensitizes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Selective multi-kinase inhibition sensitizes...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Antinéoplasiques immunologiques › Inhibiteurs de points de contrôle immunitaires › Selective multi-kinase inhibition sensitizes...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Selective multi-kinase inhibition sensitizes...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › Selective multi-kinase inhibition sensitizes...