The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9.
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.
Breast Cancer Biology Group, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
Richard
R
Beatson
Breast Cancer Biology Group, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
Virginia
V
Tajadura-Ortega
CAR Mechanics Group, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
Daniela
D
Achkova
Breast Cancer Biology Group, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
Gianfranco
G
Picco
Breast Cancer Biology Group, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
Theodora-Dorita
TD
Tsourouktsoglou
Cell Culture Technology Group, University of Bielefeld, Bielefeld, Germany.
Sandra
S
Klausing
Breast Cancer Biology Group, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
Matthew
M
Hillier
CAR Mechanics Group, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
John
J
Maher
Cell Culture Technology Group, University of Bielefeld, Bielefeld, Germany.
Thomas
T
Noll
School of Life Sciences, University of Dundee, Dundee, UK.
Paul R
PR
Crocker
Breast Cancer Biology Group, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
Joyce
J
Taylor-Papadimitriou
Breast Cancer Biology Group, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
Joy M
JM
Burchell
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers; D002454:Cell Differentiation; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D006031:Glycosylation; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018396:Mucin-1 / Q000378:metabolism*; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011485:Protein Binding; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000276:immunology*
D015703:Antigens, CD; D015415:Biomarkers; D018396:Mucin-1; C412227:SIGLEC9 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases