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

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224 Citations (Scopus)
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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 languageEnglish
Pages (from-to)1273-1281
JournalNature Immunology
Volume17
Issue number11
Early online date5 Sept 2016
DOIs
Publication statusPublished - 1 Nov 2016

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