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

Ernesto Rodriguez, Kelly Boelaars, Kari Brown, R. J. Eveline Li, Laura Kruijssen, Sven C. M. Bruijns, Thomas Ee, Sjoerd T. T. Schetters, Matheus H. W. Crommentuijn, Joost C. Horst, Nicole C. T. Grieken, Sandra J. Vliet, Geert Kazemier, Elisa Giovannetti, Juan J. Garcia-Vallejo and Yvette Kooyk ()
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Ernesto Rodriguez: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute
Kelly Boelaars: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute
Kari Brown: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute
R. J. Eveline Li: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute
Laura Kruijssen: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute
Sven C. M. Bruijns: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute
Thomas Ee: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute
Sjoerd T. T. Schetters: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute
Matheus H. W. Crommentuijn: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute
Joost C. Horst: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute
Nicole C. T. Grieken: Vrije Universiteit Amsterdam, Department of Pathology
Sandra J. Vliet: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute
Geert Kazemier: Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam
Elisa Giovannetti: Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam
Juan J. Garcia-Vallejo: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute
Yvette Kooyk: Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-21550-4

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