Plenary Session
AB074. SOH24AB_235. Stromal cell-mediated immunosuppression: sialylated ligands as orchestrators of T cell and natural killer cell suppression in the tumour microenvironment of colorectal cancer
Norashikin Zakaria1, Aoise O’Neill1, Hannah Egan1, Oliver Treacy1, Jenny Che2, Li Peng2, Margaret Sheehan3, Aoife Canney3, Sean Hynes3,4, Aisling Hogan5, Aideen Ryan1
1Discipline of Pharmacology and Therapeutics, Lambe Institute for Translational Research, School of Medicine, Nursing and Health Science, University of Galway, Galway, Ireland;
2Palleon Pharmaceuticals, Waltham, MA, USA;
3Division of Anatomical Pathology, Galway University Hospital, Galway, Ireland;
4Discipline of Pathology, School of Medicine, College of Medicine, Nursing and Health Sciences, Clinical Science Institute, University of Galway, Galway, Ireland;
5Department of Colorectal Surgery, Galway University Hospital, Galway, Ireland
Background: Cancer-associated fibroblasts (CAFs) are an integral component of the tumour microenvironment and can inhibit cancer immunotherapy efficacy. Directly targeting CAFs may hold great promise in augmenting cancer treatment. However, limited understanding of the mechanisms mediating CAF immunosuppression remains an obstacle. The Siglec-sialic acid axis has emerged as a new mechanism of cancer immune evasion. This study aimed to evaluate the role of sialic acid in CAF-mediated immunosuppression in colorectal cancer (CRC).
Methods: CAFs and matched normal-associated fibroblasts (NAFs) were isolated from tumour and adjacent non-cancerous tissue, respectively (n=5). Informed consent was obtained prior to sampling. Expression of fibroblast markers [α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP)], sialic acid [α2,6-linked sialic acids (SNA-I) and α2,3-linked sialic acids (MAL-II)], and Siglec-7/9 ligands on NAFs/CAFs were analysed using flow cytometry. Immunosuppressive effects of CAFs on T cells and natural killer (NK) cells were assessed by analysing immunosuppressive/activation markers, as well as Siglec-7/9 receptor expression.
Results: CAFs expressed higher levels of sialic acid and Siglec-7/9 ligands compared to NAFs and tumour cells. CAFs also induced exhausted immunomodulatory CD8+PD1+ and CD8+Siglec-7/9+ T cell phenotypes. Furthermore, CAFs induced Siglec-7/9 on NK cells and reduced expression of the activating receptor NKG2D, leading to decreased NK cell cytotoxicity. Strikingly, de-sialylation of CAFs reversed these effects.
Conclusions: We show for the first time that CAFs can induce immunosuppressive Siglec receptor expression on T and NK cells. Our study underscores the pivotal role of sialylated ligands on CAFs in immunosuppression. Targeting the Siglec-sialic acid axis on CAFs is a promising strategy to enhance anti-tumour immunity and potentially immune checkpoint inhibition resistance in CRC.
Keywords: Colorectal cancer (CRC); cancer-associated fibroblast (CAF); sialic acid; Siglecs; immunosuppression
Acknowledgments
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-24-ab074
Cite this abstract as: Zakaria N, O’Neill A, Egan H, Treacy O, Che J, Peng L, Sheehan M, Canney A, Hynes S, Hogan A, Ryan A. AB074. SOH24AB_235. Stromal cell-mediated immunosuppression: sialylated ligands as orchestrators of T cell and natural killer cell suppression in the tumour microenvironment of colorectal cancer. Mesentery Peritoneum 2024;8:AB074.
