Drummond-Guy Olivia, Daly John, Wu Angeline, Stewart Natalie, Milne Katy, Duff Chloe, Nelson Brad H, Williams Karla C, Wisnovsky Simon
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
Deeley Research Centre, British Columbia (BC) Cancer, Victoria, BC, Canada.
Front Oncol. 2025 Mar 20;15:1520948. doi: 10.3389/fonc.2025.1520948. eCollection 2025.
Suppression of anticancer immune function is a key driver of tumorigenesis. Identifying molecular pathways that inhibit anticancer immunity is critical for developing novel immunotherapeutics. One such molecule that has recently been identified is the carbohydrate polysialic acid (polySia), whose expression is dramatically upregulated on both cancer cells and immune cells in breast cancer patient tissues. The role of polySia in the anticancer immune response, however, remains incompletely understood. In this study, we profile polySia expression on both healthy primary immune cells and on infiltrating immune cells in the tumour microenvironment (TME). These studies reveal polySia expression on multiple immune cell subsets in patient breast tumors. We find that stimulation of primary T-cells and macrophages induces a significant upregulation of polySia expression. We subsequently show that polySia is appended to a range of different carrier proteins within these immune cells. Finally, we find that selective removal of polySia can significantly potentiate killing of breast cancer cells by innate immune cells. These studies implicate polySia as a significant negative regulator of anticancer immunity.
抗癌免疫功能的抑制是肿瘤发生的关键驱动因素。识别抑制抗癌免疫的分子途径对于开发新型免疫疗法至关重要。最近发现的一种此类分子是碳水化合物多唾液酸（polySia），其在乳腺癌患者组织的癌细胞和免疫细胞上的表达均显著上调。然而，polySia在抗癌免疫反应中的作用仍未完全了解。在本研究中，我们分析了健康原代免疫细胞和肿瘤微环境（TME）中浸润免疫细胞上的polySia表达。这些研究揭示了患者乳腺肿瘤中多个免疫细胞亚群上的polySia表达。我们发现，对原代T细胞和巨噬细胞的刺激会导致polySia表达显著上调。随后我们表明，polySia附着于这些免疫细胞内一系列不同的载体蛋白上。最后，我们发现选择性去除polySia可显著增强先天免疫细胞对乳腺癌细胞的杀伤作用。这些研究表明polySia是抗癌免疫的重要负调节因子。
