Stromal cells modulate innate immune cell phenotype and function in colorectal cancer via the Sialic acid/Siglec axis

作者：Aoise O’Neill, Norashikin Zakaria, Hannah Egan, Shania M. Corry, Courtney Bull, Niamh Leonard, Clodagh O’Meara, Linda Howard, Anastasija Walsh, Eileen Reidy, Jenny Che, Peng Li, Lizhi Cao, Laurence J. Egan, Thomas Ritter, Margaret Sheehan, Aoife Canney, Kevin Culligan, Aisling Hogan, Seán O. Hynes, Philip D. Dunne, Michael O’Dwyer, Oliver Treacy, Aideen E. Ryan · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.03.14.642985 · 被引用次数：1 · 研究领域：Glycosylation and Glycoproteins Research、Galectins and Cancer Biology、Immune Response and Inflammation

Abstract Background The immunosuppressive tumour microenvironment (TME) reduces immune response effectiveness in stromal-rich tumours, including CMS4 colorectal cancer (CRC). Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote cancer progression by suppressing anti-tumour immune responses. Hypersialylation of glycans on tumours engages Siglec receptors on immune cells, driving immune dysfunction, but its role in stromal-mediated immunosuppression remains unclear. Methods Sialic acids and Siglec ligands were measured on CRC tissue, primary human CAFs, and tumour-conditioned-mesenchymal stromal cells (MSC TCS ) and CAF using immunohistochemistry and flow cytometry. The effect of stromal cell sialylation on macrophages and NK cells was assessed in ex vivo primary stromal and immune cell co-cultures and expression of Siglec-10 and immune cell phenotype markers and function were measured by flow cytometry. Using an immunocompetent Balb/c CT26 mouse model, we induced tumours with/without conditioned stromal cells, with/without pre-treatment of stromal cells with sialyltransferase inhibitor (3FAX) or sialidase (E610). We assessed the effect of stromal cell sialylation on macrophages and NK cells in the tumour and secondary lymphoid tissues by flow cytometry. Results Stromal cells, including CAFs, in CRC tumours are highly sialylated compared to epithelial cancer cells and are associated with high expression of ST6GalNAC6 . Genetic knockdown ...