Interactions between Siglec-7/9 receptors and ligands influence NK cell-dependent tumor immunosurveillance

J Clin Invest. 2014 Apr;124(4):1810-20. doi: 10.1172/JCI65899. Epub 2014 Feb 24.

Abstract

Alteration of the surface glycosylation pattern on malignant cells potentially affects tumor immunity by directly influencing interactions with glycan-binding proteins (lectins) on the surface of immunomodulatory cells. The sialic acid-binding Ig-like lectins Siglec-7 and -9 are MHC class I-independent inhibitory receptors on human NK cells that recognize sialic acid-containing carbohydrates. Here, we found that the presence of Siglec-9 defined a subset of cytotoxic NK cells with a mature phenotype and enhanced chemotactic potential. Interestingly, this Siglec-9+ NK cell population was reduced in the peripheral blood of cancer patients. Broad analysis of primary tumor samples revealed that ligands of Siglec-7 and -9 were expressed on human cancer cells of different histological types. Expression of Siglec-7 and -9 ligands was associated with susceptibility of NK cell-sensitive tumor cells and, unexpectedly, of presumably NK cell-resistant tumor cells to NK cell-mediated cytotoxicity. Together, these observations have direct implications for NK cell-based therapies and highlight the requirement to consider both MHC class I haplotype and tumor-specific glycosylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Antigens, Differentiation, Myelomonocytic / metabolism*
  • Antigens, Tumor-Associated, Carbohydrate / metabolism
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Female
  • Glycosylation
  • HeLa Cells
  • Humans
  • Immunity, Innate
  • K562 Cells
  • Killer Cells, Natural / classification
  • Killer Cells, Natural / immunology*
  • Lectins / metabolism*
  • Ligands
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Monitoring, Immunologic*
  • Neoplasms / immunology*
  • Sialic Acid Binding Immunoglobulin-like Lectins / metabolism*

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Antigens, Tumor-Associated, Carbohydrate
  • Lectins
  • Ligands
  • SIGLEC7 protein, human
  • SIGLEC9 protein, human
  • Sialic Acid Binding Immunoglobulin-like Lectins