Galectin-1 induces a tumor-associated macrophage phenotype and upregulates indoleamine 2,3-dioxygenase-1
Asha M. Rudjord-Levann,
Zilu Ye,
Lise Hafkenscheid,
Sabrina Horn,
Renske Wiegertjes,
Mathias A.I. Nielsen,
Ming Song,
Caroline B.K. Mathiesen,
Jesse Stoop,
Sean Stowell,
Per Thor Straten,
Hakon Leffler,
Sergey Y. Vakhrushev,
Sally Dabelsteen,
Jesper V. Olsen,
Hans H. Wandall
Affiliations
Asha M. Rudjord-Levann
Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Zilu Ye
Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Lise Hafkenscheid
Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Sabrina Horn
Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Renske Wiegertjes
Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Mathias A.I. Nielsen
Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Ming Song
Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Caroline B.K. Mathiesen
Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Jesse Stoop
Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Sean Stowell
Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Per Thor Straten
Center for Cancer Immune Therapy, Copenhagen University Hospital, Herlev, Denmark
Hakon Leffler
Division of Microbiology, Immunology and Glycobiology, BMC C1228b, Klinikgatan 28, Lund, Sweden
Sergey Y. Vakhrushev
Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Sally Dabelsteen
Department of Oral Medicine and Pathology, School of Dentistry, University of Copenhagen, Copenhagen, Denmark
Jesper V. Olsen
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Hans H. Wandall
Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Corresponding author
Summary: Galectins are a group of carbohydrate-binding proteins with a presumed immunomodulatory role and an elusive function on antigen-presenting cells. Here we analyzed the expression of galectin-1 and found upregulation of galectin-1 in the extracellular matrix across multiple tumors. Performing an in-depth and dynamic proteomic and phosphoproteomic analysis of human macrophages stimulated with galectin-1, we show that galectin-1 induces a tumor-associated macrophage phenotype with increased expression of key immune checkpoint protein programmed cell death 1 ligand 1 (PD-L1/CD274) and immunomodulator indoleamine 2,3-dioxygenase-1 (IDO1). Galectin-1 induced IDO1 and its active metabolite kynurenine in a dose-dependent manner through JAK/STAT signaling. In a 3D organotypic tissue model system equipped with genetically engineered tumorigenic epithelial cells, we analyzed the cellular source of galectin-1 in the extracellular matrix and found that galectin-1 is derived from epithelial and stromal cells. Our results highlight the potential of targeting galectin-1 in immunotherapeutic treatment of human cancers.
