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

Nat Immunol. 2016 Nov;17(11):1273-1281. doi: 10.1038/ni.3552. Epub 2016 Sep 5.

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.

MeSH terms

  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Biomarkers
  • Cell Differentiation
  • Cell Line
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression
  • Glycosylation
  • Humans
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Mucin-1 / metabolism*
  • Myeloid Cells / cytology
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Phenotype
  • Protein Binding
  • Sialic Acid Binding Immunoglobulin-like Lectins / genetics
  • Sialic Acid Binding Immunoglobulin-like Lectins / metabolism*
  • Tumor Microenvironment / immunology*

Substances

  • Antigens, CD
  • Biomarkers
  • Mucin-1
  • SIGLEC9 protein, human
  • Sialic Acid Binding Immunoglobulin-like Lectins
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases