TY - JOUR
T1 - Sialic acids in pancreatic cancer cells drive tumour-associated macrophage differentiation via the Siglec receptors Siglec-7 and Siglec-9
AU - Rodriguez, Ernesto
AU - Boelaars, Kelly
AU - Brown, Kari
AU - Eveline Li, R. J.
AU - Kruijssen, Laura
AU - Bruijns, Sven C. M.
AU - van Ee, Thomas
AU - Schetters, Sjoerd T. T.
AU - Crommentuijn, Matheus H. W.
AU - van der Horst, Joost C.
AU - van Grieken, Nicole C. T.
AU - van Vliet, Sandra J.
AU - Kazemier, Geert
AU - Giovannetti, Elisa
AU - Garcia-Vallejo, Juan J.
AU - van Kooyk, Yvette
N1 - Funding Information: The authors would like to acknowledge the Microscopy and Cytometry Core Facility at the Amsterdam UMC-Location VUmc for providing assistance in cytometry experiments. This work is financially supported by Immunoshape (MSCA-ITN-2014-ETN No. 642870) to E.R.; by SPINOZA prize to E.R. and Y.K.; by the European Research Council (ERC-339977-Glycotreat) to S.T.T.S. and Y.K.; by KWF VU2014-7200 to K.Bo.; by the AIRC Start-Up grant (to E.G.). Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85101567909&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-021-21550-4
DO - https://doi.org/10.1038/s41467-021-21550-4
M3 - Article
C2 - 33627655
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1270
ER -