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

Richard Beatson, Virginia Tajadura-Ortega, Daniela Achkova, Gianfranco Picco, Theodora-Dorita Tsourouktsoglou, Sandra Klausing, Matthew Hillier, John Maher, Thomas Noll, Paul R. Crocker, Joyce Taylor-Papadimitriou, Joy M. Burchell (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

95 Citations (Scopus)

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
Number of pages9
JournalNature Immunology
Volume17
Issue number11
Early online date5 Sep 2016
DOIs
Publication statusPublished - Nov 2016

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