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

作者：Laubli Heinz; Pearce Oliver M T; Schwarz Flavio; Siddiqui Shoib S; Deng Lingquan; Stanczak Michal A; Deng Liwen; Verhagen Andrea; Secrest Patrick; Lusk Chrissy; Schwartz Ann G; Varki Nissi M; Bui Jack D; Varki Ajit^*

来源：Proceedings of the National Academy of Sciences, 2014, 111(39): 14211-14216.

DOI：10.1073/pnas.1409580111

• hypersialylation
• tumor-associated macrophages
• tumor-associated neutrophils
• immune evasion
• tumor-associated inflammation

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.

• 出版日期2014-9-30