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

doi:10.1016/j.isci.2023.106984

Galectin-1 induces a tumor-associated macrophage phenotype and upregulates indoleamine 2,3-dioxygenase-1

iScience. 2023 May 27;26(7):106984. doi: 10.1016/j.isci.2023.106984. eCollection 2023 Jul 21.

Authors

Asha M Rudjord-Levann¹, Zilu Ye^{1

2}, Lise Hafkenscheid¹, Sabrina Horn¹, Renske Wiegertjes¹, Mathias A I Nielsen¹, Ming Song¹, Caroline B K Mathiesen¹, Jesse Stoop¹, Sean Stowell³, Per Thor Straten⁴, Hakon Leffler⁵, Sergey Y Vakhrushev¹, Sally Dabelsteen⁶, Jesper V Olsen², Hans H Wandall¹

Affiliations

¹ Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
² Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³ Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁴ Center for Cancer Immune Therapy, Copenhagen University Hospital, Herlev, Denmark.
⁵ Division of Microbiology, Immunology and Glycobiology, BMC C1228b, Klinikgatan 28, Lund, Sweden.
⁶ Department of Oral Medicine and Pathology, School of Dentistry, University of Copenhagen, Copenhagen, Denmark.

Abstract

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.

Keywords: Cancer; Immunology.