TY - JOUR
T1 - The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9
AU - Beatson, Richard
AU - Tajadura-Ortega, Virginia
AU - Achkova, Daniela
AU - Picco, Gianfranco
AU - Tsourouktsoglou, Theodora-Dorita
AU - Klausing, Sandra
AU - Hillier, Matthew
AU - Maher, John
AU - Noll, Thomas
AU - Crocker, Paul R.
AU - Taylor-Papadimitriou, Joyce
AU - Burchell, Joy M.
N1 - We thank V. Corrigall (King's College London) for tocilizumab; and N. O'Reilly for the lyophilization of samples. Supported by Breast Cancer Now (2011NovPR-43), the Medical Research Council (MR/J007196/1), the Department the Experimental Cancer Medicine Centre at King's College London, the National Institute for Health Research Biomedical Research Centre based at Guy's and St Thomas’ NHS Foundation Trust and King's College London.
PY - 2016/11
Y1 - 2016/11
N2 - Siglec-9 is a sialic-acid-binding lectin expressed predominantly on myeloid cells. Aberrant glycosylation occurs in essentially all types of cancers and results in increased sialylation. Thus, when the mucin MUC1 is expressed on cancer cells, it is decorated by multiple short, sialylated O-linked glycans (MUC1-ST). Here we found that this cancer-specific MUC1 glycoform, through engagement of Siglec-9, 'educated' myeloid cells to release factors associated with determination of the tumor microenvironment and disease progression. Moreover, MUC1-ST induced macrophages to display a tumor-associated macrophage (TAM)-like phenotype, with increased expression of the checkpoint ligand PD-L1. Binding of MUC1-ST to Siglec-9 did not activate the phosphatases SHP-1 or SHP-2 but, unexpectedly, induced calcium flux that led to activation of the kinases MEK-ERK. This work defines a critical role for aberrantly glycosylated MUC1 and identifies an activating pathway that follows engagement of Siglec-9.
AB - Siglec-9 is a sialic-acid-binding lectin expressed predominantly on myeloid cells. Aberrant glycosylation occurs in essentially all types of cancers and results in increased sialylation. Thus, when the mucin MUC1 is expressed on cancer cells, it is decorated by multiple short, sialylated O-linked glycans (MUC1-ST). Here we found that this cancer-specific MUC1 glycoform, through engagement of Siglec-9, 'educated' myeloid cells to release factors associated with determination of the tumor microenvironment and disease progression. Moreover, MUC1-ST induced macrophages to display a tumor-associated macrophage (TAM)-like phenotype, with increased expression of the checkpoint ligand PD-L1. Binding of MUC1-ST to Siglec-9 did not activate the phosphatases SHP-1 or SHP-2 but, unexpectedly, induced calcium flux that led to activation of the kinases MEK-ERK. This work defines a critical role for aberrantly glycosylated MUC1 and identifies an activating pathway that follows engagement of Siglec-9.
UR - http://europepmc.org/abstract/MED/27595232
U2 - 10.1038/ni.3552
DO - 10.1038/ni.3552
M3 - Article
C2 - 27595232
SN - 1529-2908
VL - 17
SP - 1273
EP - 1281
JO - Nature Immunology
JF - Nature Immunology
IS - 11
ER -
