Stromal cell sialylation suppresses T cells in inflammatory tumour microenvironments: A new tumour stromal cell immune checkpoint?

作者：Hannah Egan, Oliver Treacy, Kevin Lynch, Niamh Leonard, Grace O’Malley, Kim De Veirman, Karin Vanderkerken, Michael Craughwell, Laurence J. Egan, Thomas Ritter, Aisling Hogan, Keara L. Redmond, Margaret Sheehan, Aoife Canney, Seán O. Hynes, Emma Kerr, Philip D. Dunne, Michael O’Dwyer, Aideen E. Ryan · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2021 · DOI：10.1101/2021.06.18.447879 · 被引用次数：4 · 研究领域：Glycosylation and Glycoproteins Research、Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses

Abstract Immunosuppressive tumour microenvironments (TME) reduce the effectiveness of immune responses in cancer. Non-haematopoietic mesenchymal stromal cells (MSC), the precursor to cancer associated fibroblasts (CAFs), dictate tumour progression by enhancing immune cell suppression. Hyper-sialylation of glycans promotes immune evasion in cancer, but the role of sialyation in stromal cell-mediated immunosuppression is unknown. Here we study changes in sialyltransferase (ST) enzymes and associated surface expressed sialic acid in stromal cells following inflammatory and tumour secretome conditioning. We show that tumour conditioned stromal cells have increased levels of sialyltransferases, α2,3/6 linked sialic acid and siglec ligands. In tumour models of solid (colorectal cancer) and haematological (multiple myeloma) stromal rich tumours, stromal cell sialylation is associated with enhanced immunosuppression. Using datasets and patient samples, we confirm that targeting sialylation in tumour stromal cells reverses immune cell exhaustion. Targeting stromal cell sialylation may represent a novel immune checkpoint to reactivate anti-tumour immunity.