Engagement of myelomonocytic Siglecs by tumor-associated ligands modulates the innate immune response to cancer

Heinz Läubli, Oliver M T Pearce, Flavio Schwarz, Shoib S Siddiqui, Lingquan Deng, Michal A Stanczak, Liwen Deng, Andrea Verhagen, Patrick Secrest, Chrissy Lusk, Ann G Schwartz, Nissi M Varki, Jack D Bui, Ajit Varki

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99 Citations (Scopus)


Certain pathogenic bacteria are known to modulate the innate immune response by decorating themselves with sialic acids, which can engage the myelomonocytic lineage inhibitory receptor Siglec-9, thereby evading immunosurveillance. We hypothesized that the well-known up-regulation of sialoglycoconjugates by tumors might similarly modulate interactions with innate immune cells. Supporting this hypothesis, Siglec-9-expressing myelomonocytic cells found in human tumor samples were accompanied by a strong up-regulation of Siglec-9 ligands. Blockade of Siglec-9 enhanced neutrophil activity against tumor cells in vitro. To investigate the function of inhibitory myelomonocytic Siglecs in vivo we studied mouse Siglec-E, the murine functional equivalent of Siglec-9. Siglec-E-deficient mice showed increased in vivo killing of tumor cells, and this effect was reversed by transgenic Siglec-9 expression in myelomonocytic cells. Siglec-E-deficient mice also showed enhanced immunosurveillance of autologous tumors. However, once tumors were established, they grew faster in Siglec-E-deficient mice. In keeping with this, Siglec-E-deficient macrophages showed a propensity toward a tumor-promoting M2 polarization, indicating a secondary role of CD33-related Siglecs in limiting cancer-promoting inflammation and tumor growth. Thus, we define a previously unidentified impact of inhibitory myelomonocytic Siglecs in cancer biology, with distinct roles that reflect the dual function of myelomonocytic cells in cancer progression. In keeping with this, a human polymorphism that reduced Siglec-9 binding to carcinomas was associated with improved early survival in non-small-cell lung cancer patients, which suggests that Siglec-9 might be therapeutically targeted within the right time frame and stage of disease.

Original languageEnglish
Pages (from-to)14211-6
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number39
Publication statusPublished - 30 Sept 2014


  • Animals
  • Antigens, CD/genetics
  • Antigens, Differentiation, B-Lymphocyte/genetics
  • Carcinoma, Non-Small-Cell Lung/genetics
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunity, Innate
  • Ligands
  • Lung Neoplasms/genetics
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Monocytes/immunology
  • Neoplasms/immunology
  • Neutrophil Activation
  • Polymorphism, Single Nucleotide
  • Sialic Acid Binding Immunoglobulin-like Lectins/genetics
  • Tumor Microenvironment/immunology


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