Galectin-1 upregulates IDO1 and PD-L1 and induces a tolerogenic tumor-associated macrophage phenotype

Abstract

Galectins are a group of carbohydrate-binding proteins with a presumed immunomodulatory role and an elusive function on antigen-presenting cells. Here we used an in-depth and dynamic proteomic and phosphoproteomic analysis of human macrophages stimulated with galectin-1 and show that galectin-1 induces a tolerogenic 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 dependent on JAK/STAT signaling. Analyzing the expression of galectin-1 showed that galectin-1 is upregulated across multiple tumors and in a 3D organotypic model system equipped with genetically engineered tumorigenic epithelial cells we find that the tumor-associated galectin-1 is derived from both epithelial and stromal cells. Our results highlight the potential of targeting galectin-1 in immunotherapeutic treatment of human cancers.