2. Academic Validation
  3. DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer

DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer

  • Gut. 2024 Jun 4:gutjnl-2023-331854. doi: 10.1136/gutjnl-2023-331854.
Anna Brichkina 1 2,  Miriam Ems 1,  Roman Suezov 1,  Rajeev Singh 1,  Veronika Lutz 3,  Felix S R Picard 3,  Andrea Nist 4,  Thorsten Stiewe 4 5,  Johannes Graumann 6 7,  Michael Daude 8,  Wibke E Diederich 8 9,  Florian Finkernagel 10,  Ho-Ryun Chung 11,  Detlef K Bartsch 12,  Katrin Roth 13,  Corinna Keber 14,  Carsten Denkert 14,  Magdalena Huber 3,  Thomas M Gress 15,  Matthias Lauth 16
Affiliations

Affiliations

  • 1 Department of Gastroenterology Endocrinology and Metabolism, Center for Tumor and Immune Biology, Marburg, Germany.
  • 2 Present address: Institute of Systems Immunology, Center for Tumor and Immune Biology, Marburg, Germany.
  • 3 Institute of Systems Immunology, Philipps-Universitat Marburg, Marburg, Hessen, Germany.
  • 4 Genomics Core Facility, Philipps University Marburg, Marburg, Germany.
  • 5 Institute for Molecular Oncology, German Center for Lung Research (DZL), Marburg, Germany.
  • 6 Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 7 Institute of Translational Proteomics, Philipps University, Marburg, Germany.
  • 8 Medicinal Chemistry Core Facility, Philipps University Marburg, Marburg, Germany.
  • 9 Department of Medicinal chemistry, Center for Tumor and Immune Biology, Marburg, Germany.
  • 10 Bioinformatics Core Facility, Center for Tumor and Immune Biology, Marburg, Germany.
  • 11 Institute for Medical Bioinformatics and Biostatistics, Institute for Molecular Biology and Tumor Research, Marburg, Germany.
  • 12 Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany.
  • 13 Cell Imaging Core Facility, Center for Tumor Biology and Immunology, Philipps-University Marburg, Marburg, Hessen, Germany.
  • 14 Institute of Pathology, University Hospital of Giessen-Marburg, Marburg, Germany.
  • 15 Department of Gastroenterology, Endocrinology and Metabolism, Center for Tumor and Immune Biology, Marburg, Germany.
  • 16 Department of Gastroenterology Endocrinology and Metabolism, Center for Tumor and Immune Biology, Marburg, Germany lauth@staff.uni-marburg.de.
PMID: 38834297 DOI: 10.1136/gutjnl-2023-331854
Abstract

Objective: Highly malignant pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant immunosuppressive and fibrotic tumour microenvironment (TME). Future therapeutic attempts will therefore demand the targeting of tumours and stromal compartments in order to be effective. Here we investigate whether dual specificity and tyrosine phosphorylation-regulated kinase 1B (DYRK1B) fulfil these criteria and represent a promising Anticancer target in PDAC.

Design: We used transplantation and autochthonous mouse models of PDAC with either genetic Dyrk1b loss or pharmacological DYRK1B inhibition, respectively. Mechanistic interactions between tumour cells and macrophages were studied in direct or indirect co-culture experiments. Histological analyses used tissue microarrays from patients with PDAC. Additional methodological approaches included bulk mRNA Sequencing (transcriptomics) and proteomics (secretomics).

Results: We found that DYRK1B is mainly expressed by pancreatic epithelial Cancer cells and modulates the influx and activity of TME-associated macrophages through effects on the Cancer cells themselves as well as through the tumour secretome. Mechanistically, genetic ablation or pharmacological inhibition of DYRK1B strongly attracts tumoricidal macrophages and, in addition, downregulates the phagocytosis checkpoint and 'don't eat me' signal CD24 on Cancer cells, resulting in enhanced tumour cell phagocytosis. Consequently, tumour cells lacking DYRK1B hardly expand in transplantation experiments, despite their rapid growth in culture. Furthermore, combining a small-molecule DYRK1B-directed therapy with mammalian target of rapamycin inhibition and conventional chemotherapy stalls the growth of established tumours and results in a significant extension of life span in a highly aggressive autochthonous model of PDAC.

Conclusion: In light of DYRK inhibitors currently entering clinical phase testing, our data thus provide a novel and clinically translatable approach targeting both the Cancer cell compartment and its microenvironment.

Keywords

immunotherapy; macrophages; molecular carcinogenesis; pancreatic cancer; pancreatic tumours.

Figures
Products
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    Product Name
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  • HY-50710
    99.55%, Specific mTOR Inhibitor