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Interactions between Siglec-7/9 receptors and ligands influence NK cell–dependent tumor immunosurveillance
Camilla Jandus, … , Christian Münz, Stephan von Gunten
Camilla Jandus, … , Christian Münz, Stephan von Gunten
Published February 24, 2014
Citation Information: J Clin Invest. 2014;124(4):1810-1820. https://doi.org/10.1172/JCI65899.
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Research Article Immunology

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

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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.

Authors

Camilla Jandus, Kayluz Frias Boligan, Obinna Chijioke, He Liu, Meike Dahlhaus, Thomas Démoulins, Christoph Schneider, Marc Wehrli, Robert E. Hunger, Gabriela M. Baerlocher, Hans-Uwe Simon, Pedro Romero, Christian Münz, Stephan von Gunten

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Figure 1

Human tumor cells express variable, but significant, levels of Siglec-7 and -9 ligands.

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Human tumor cells express variable, but significant, levels of Siglec-7 ...
(A–C and E) Immunofluorescence binding studies by flow cytometry (A and C) or immunofluorescence confocal microscopy (B and E) using recombinant Siglec-Fc (human IgG1) fusion proteins coupled to secondary PE-conjugated (Fab′)2 goat anti-human Fc antibody. (A) Broad analysis of ligand expression to Siglec-7 and -9 on different tumor cell lines, as well as on primary melanocytes (n = 2) and PBMCs (n = 9) from healthy donors for comparison. Values are expressed as geometric mean fluorescence intensity (GMFI) ratio of specific staining compared with secondary antibody only. (B) Expression of Siglec-7 and -9 ligands on A375 melanoma cells was localized to the cell surface. Staining was lost upon neuraminidase treatment (sialic acid dependency). Original magnification, ×630. (C) Expression levels of Siglec-7 and -9 ligands on CLL and AML cells, as revealed by flow cytometric analysis. Histograms are representative of 3 CLL and 3 AML patients. (D) Lectin immunohistochemistry for Siglec-7 and -9 ligand expression in paraffin-embedded tissues representative of melanoma, BCC, SCC, and CTCL sections. Scale bars: 100 μm (melanoma, BCC, and SCC); 50 μm (CTCL). (E) Paraffin-embedded primary tissue biopsy sections of malignant melanoma lesions in epidermal skin layers, costained for the melanoma marker Melan-A and Siglec-7 or Siglec-9 ligands. Scale bars: 50 μm. Data are representative of at least 2 (B), 3 (D), or 5 (E) independent experiments.
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