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, Courtney Bull, Hannah Egan, Shania M. Corry, 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：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2025-012491 · 被引用次数：9 · 研究领域：Glycosylation and Glycoproteins Research、Immune cells in cancer、Cancer Cells and Metastasis

Background The immunosuppressive tumor microenvironment reduces immune response effectiveness in stromal-rich tumors, including consensus molecular subtype 4 colorectal cancer (CRC). Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote cancer progression by suppressing anti-tumor immune responses. Hypersialylation of glycans on tumors engages Siglec receptors on immune cells, driving immune dysfunction, but its role in stromal-mediated suppression of innate immunity remains unclear. Methods Sialylation, Sialic acids and Siglec ligands were measured on CRC tissue, primary human normal-associated fibroblasts (NAFs), CAFs, and tumor-conditioned MSCs (MSC TCS ) using transcriptional profiles, immunohistochemistry and flow cytometry, respectively. The effect of stromal cell sialylation on macrophages and NK cells was assessed in ex vivo human primary stromal and immune cell co-cultures, and expression of Siglec-10 and immune cell phenotype markers and function was measured by flow cytometry and real-time imaging. Using an immunocompetent Balb/c CT26 mouse model, we induced tumors with/without conditioned stromal cells, with/without pretreatment 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 tumor and secondary lymphoid tissues by flow cytometry. Results Stromal cells, including CAFs, in CRC tumors are highly sialylated compar...