The mucin MUC1 modulates the tumor immune microenvironment through the engagement of Siglec-9

Richard Beatson; Virginia Tajadura-Ortega; Daniela Yordanova Achkova; Gianfranco Picco; Theodora-Dorita  Tsourouktsoglou; Sandra Klausing; Matthew Hillier; John Maher; Thomas Noll; Paul Crocker; Joyce Taylor-Papadimitriou; Joy Burchell

doi:10.1038/ni.3552

The mucin MUC1 modulates the tumor immune microenvironment through the engagement of Siglec-9

Richard Beatson, Virginia Tajadura-Ortega, Daniela Yordanova Achkova, Gianfranco Picco, Theodora-Dorita Tsourouktsoglou, Sandra Klausing, Matthew Hillier, John Maher, Thomas Noll, Paul Crocker, Joyce Taylor-Papadimitriou, Joy Burchell

Comprehensive Cancer Centre

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Abstract

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.

Original language	English
Pages (from-to)	1273-1281
Journal	Nature Immunology
Volume	17
Issue number	11
Early online date	5 Sept 2016
DOIs	https://doi.org/10.1038/ni.3552
Publication status	Published - 1 Nov 2016

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The mucin MUC1 modulates r_BEATSON_Accepted 3August2016_GREEN AAMAccepted author manuscript, 8.67 MBLicence: Unspecified

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title = "The mucin MUC1 modulates the tumor immune microenvironment through the engagement of Siglec-9",

abstract = "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.",

author = "Richard Beatson and Virginia Tajadura-Ortega and Achkova, {Daniela Yordanova} and Gianfranco Picco and Theodora-Dorita Tsourouktsoglou and Sandra Klausing and Matthew Hillier and John Maher and Thomas Noll and Paul Crocker and Joyce Taylor-Papadimitriou and Joy Burchell",

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AU - Beatson, Richard

AU - Tajadura-Ortega, Virginia

AU - Achkova, Daniela Yordanova

AU - Picco, Gianfranco

AU - Tsourouktsoglou, Theodora-Dorita

AU - Klausing, Sandra

AU - Hillier, Matthew

AU - Maher, John

AU - Noll, Thomas

AU - Crocker, Paul

AU - Taylor-Papadimitriou, Joyce

AU - Burchell, Joy

PY - 2016/11/1

Y1 - 2016/11/1

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.

U2 - 10.1038/ni.3552

DO - 10.1038/ni.3552

M3 - Article

SN - 1529-2916

VL - 17

SP - 1273

EP - 1281

JO - Nature Immunology

JF - Nature Immunology

IS - 11

ER -

The mucin MUC1 modulates the tumor immune microenvironment through the engagement of Siglec-9

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