Journal Article

Sialic acids in pancreatic cancer cells drive tumour-associated macrophage differentiation via the Siglec receptors Siglec-7 and Siglec-9

van Ee, Thomas, Garcia-Vallejo, Juan J., Schetters, Sjoerd T. T., van Vliet, Sandra J., Kazemier, Geert, Crommentuijn, Matheus H. W., Eveline Li, R. J., van Grieken, Nicole C. T., van Kooyk, Yvette, Boelaars, Kelly, van der Horst, Joost C., Bruijns, Sven C. M., Giovannetti, Elisa, Brown, Kari, Kruijssen, Laura, Rodriguez, Ernesto

2021

Overview

Changes in glycosylation during tumour progression are a key hallmark of cancer. One of the glycan moieties generally overexpressed in cancer are sialic acids, which can induce immunomodulatory properties via binding to Siglec receptors. We here show that Pancreatic Ductal Adenocarcinoma (PDAC) tumour cells present an increased sialylation that can be recognized by Siglec-7 and Siglec-9 on myeloid cells. We identified the expression of the α2,3 sialyltransferases ST3GAL1 and ST3GAL4 as main contributor to the synthesis of ligands for Siglec-7 and Siglec-9 in tumour cells. Analysing the myeloid composition in PDAC, using single cell and bulk transcriptomics data, we identified monocyte-derived macrophages as contributors to the poor clinical outcome. Tumour-derived sialic acids dictate monocyte to macrophage differentiation via signalling through Siglec-7 and Siglec-9. Moreover, triggering of Siglec-9 in macrophages reduce inflammatory programmes, while increasing PD-L1 and IL-10 expression, illustrating that sialic acids modulate different myeloid cells. This work highlights a critical role for sialylated glycans in controlling immune suppression and provides new potential targets for cancer immunotherapy in PDAC. Alterations in glycosylation in tumours facilitate tumour progression. Here, the authors show that pancreatic ductal adenocarcinomas present increased sialylation, which stimulates the polarisation of monocytes via Siglec receptors, resulting in the generation of immune suppressive tumour associated macrophages.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/63 / 38 / 631/45/221 / 631/67/1504/1713 / Acids / Adenocarcinoma / Antigens, CD - genetics / Antigens, CD - metabolism / Antigens, Differentiation, Myelomonocytic - genetics / Antigens, Differentiation, Myelomonocytic - metabolism / Cancer / Cancer immunotherapy / Cell differentiation / Cell Differentiation - drug effects / Cell Line, Tumor / Clustered Regularly Interspaced Short Palindromic Repeats - genetics / Enzyme-Linked Immunosorbent Assay / Flow Cytometry / Glycan / Glycosylation / Humanities and Social Sciences / Humans / Immunomodulation / Immunotherapy / Inflammation / Interleukin 10 / Lectins - genetics / Lectins - metabolism / Macrophages / Macrophages - cytology / Macrophages - drug effects / Macrophages - metabolism / Monocytes / Monocytes - cytology / Monocytes - drug effects / Monocytes - metabolism / multidisciplinary / Myeloid cells / Pancreas - metabolism / Pancreatic cancer / Pancreatic Neoplasms / Pancreatic Neoplasms - metabolism / PD-L1 protein / Phosphorylation - drug effects / Polysaccharides / Receptor mechanisms / Receptors / Science / Science (multidisciplinary) / Sialic Acid Binding Immunoglobulin-like Lectins - genetics / Sialic Acid Binding Immunoglobulin-like Lectins - metabolism / Sialic acids / Sialic Acids - pharmacology / Tumors