Rudjord-Levann Asha M, Ye Zilu, Hafkenscheid Lise, Horn Sabrina, Wiegertjes Renske, Nielsen Mathias A I, Song Ming, Mathiesen Caroline B K, Stoop Jesse, Stowell Sean, Straten Per Thor, Leffler Hakon, Vakhrushev Sergey Y, Dabelsteen Sally, Olsen Jesper V, Wandall Hans H
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.
iScience. 2023 May 27;26(7):106984. doi: 10.1016/j.isci.2023.106984. eCollection 2023 Jul 21.
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.
半乳糖凝集素是一类碳水化合物结合蛋白，推测具有免疫调节作用，但其在抗原呈递细胞上的功能尚不明确。在此，我们分析了半乳糖凝集素-1的表达情况，发现多种肿瘤的细胞外基质中半乳糖凝集素-1表达上调。通过对用半乳糖凝集素-1刺激的人巨噬细胞进行深入的动态蛋白质组学和磷酸蛋白质组学分析，我们发现半乳糖凝集素-1可诱导肿瘤相关巨噬细胞表型，关键免疫检查点蛋白程序性细胞死亡1配体1（PD-L1/CD274）和免疫调节剂吲哚胺2,3-双加氧酶-1（IDO1）的表达增加。半乳糖凝集素-1通过JAK/STAT信号通路以剂量依赖性方式诱导IDO1及其活性代谢产物犬尿氨酸。在配备了基因工程致瘤上皮细胞的三维器官型组织模型系统中，我们分析了细胞外基质中半乳糖凝集素-1的细胞来源，发现半乳糖凝集素-1来源于上皮细胞和基质细胞。我们的结果突出了靶向半乳糖凝集素-1在人类癌症免疫治疗中的潜力。
