Scientific Session
AB081. SOH25_AB_252. Cancer-associated fibroblasts modulate immune cell function via sialic acid-siglec axis in colorectal cancer
Norashikin Zakaria1, Aoise O’Neill1, Anastasija Walsh1, Lei Lei1, Oliver Treacy1, Kevin Culligan2, Margaret Sheehan2, Aoife Canney2, Sean Hynes2,3, Aisling Hogan4, Aideen Ryan1
1Discipline of Pharmacology and Therapeutics, Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Science University of Galway, Galway, Ireland;
2Division of Anatomical Pathology, Galway University Hospital, Galway, Ireland;
3Discipline of Pathology, School of Medicine, College of Medicine, Nursing and Health Sciences, Clinical Science Institute, University of Galway, Galway, Ireland;
4Department of Colorectal Surgery, Galway University Hospital, Galway, Ireland
Background: CMS4 colorectal cancer (CRC) has poor overall survival and resistant to immunotherapy due to high mesenchymal stromal infiltration including cancer-associated fibroblast (CAF). Targeting CAFs may improve treatment, but mechanisms of CAF-mediated immunosuppression remain unclear. The Siglec-7/9-sialic acid axis has emerged as a novel immune evasion mechanism and its expression correlates with reduced patient survival in CMS4 tumours. This study investigates CAF-driven immunosuppression of innate immune cells via Siglec-7/9 interactions in CRC.
Methods: CAFs and normal-associated fibroblasts (NAFs) were isolated from tumour and adjacent non-cancerous tissue, respectively. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors or CRC patients. All human samples were collected with ethical approval and patient consent. Siglec-7/9 ligands on CAF/NAF and receptors on PBMCs or natural killer (NK) cells were analysed by flow cytometry. NK cell phenotype and function were assessed in ex vivo co-culture assays, with CAFs/NAFs pre-treatment using sialyltransferase inhibitor (SI) or sialidase.
Results: Primary CAF/NAF are characterized by αSMA, PAF, PDPN and PDGFRα expression. CAFs exhibited higher Siglec-7/9 ligands expression than NAFs, which decreased with SI or Sialidase treatment, confirming their sialylation. NK cells co-cultured with CAFs showed an exhaustive phenotype, with increased Siglec-7/9, reduced NKG2D expression and impaired cytotoxicity against CRC cells. SI and Sialidase treatment reversed these effects.
Conclusions: This study reveals that CAF-derived sialylation suppresses NK cell function in CRC. Targeting Siglec-sialic acid axis on CAFs offer promising strategy to restore NK cell-mediated anti-tumour immunity in CRC.
Keywords: Colorectal cancer (CRC); cancer-associated fibroblast (CAF); Siglecs; natural killer cell (NK cell); immunosuppression
Acknowledgments
None.
Funding: None.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
doi: 10.21037/map-25-ab081
Cite this abstract as: Zakaria N, O’Neill A, Walsh A, Lei L, Treacy O, Culligan K, Sheehan M, Canney A, Hynes S, Hogan A, Ryan A. AB081. SOH25_AB_252. Cancer-associated fibroblasts modulate immune cell function via sialic acid-siglec axis in colorectal cancer. Mesentery Peritoneum 2025;9:AB081.
