Lectin Galactoside-binding Soluble 3 Binding Protein (LGALS3BP) Is a Tumor-associated Immunomodulatory Ligand for CD33-related Siglecs

Heinz Läubli,Frederico Alisson-Silva,Michal A Stanczak,Shoib S Siddiqui,Liwen Deng,Andrea Verhagen,Nissi Varki,Ajit Varki

doi:10.1074/jbc.m114.593129

Abstract

Lectin galactoside-binding soluble 3 binding protein (LGALS3BP, also called Mac-2 binding protein) is a heavily glycosylated secreted molecule that has been shown previously to be up-regulated in many cancers and has been implicated in tumor metastatic processes, as well as in other cell adhesion and immune functions. The CD33-related subset of sialic acid-binding immunoglobulin-like lectins (Siglecs) consists of immunomodulatory molecules that have recently been associated with the modulation of immune responses to cancer. Because up-regulation of Siglec ligands in cancer tissue has been observed, the characterization of these cancer-associated ligands that bind to inhibitory CD33-related Siglecs could provide novel targets for cancer immunomodulatory therapy. Here we used affinity chromatography of tumor cell extracts to identify LGALS3BP as a novel sialic acid-dependent ligand for human Siglec-9 and for other immunomodulatory Siglecs, such as Siglec-5 and Siglec-10. In contrast, the mouse homolog Siglec-E binds to murine LGALS3BP with lower affinity. LGALS3BP has been observed to be up-regulated in human colorectal and prostate cancer specimens, particularly in the extracellular matrix. Finally, LGALS3BP was able to inhibit neutrophil activation in a sialic acid- and Siglec-dependent manner. These findings suggest a novel immunoinhibitory function for LGALS3BP that might be important for immune evasion of tumor cells during cancer progression.

Highlights

Engagement of inhibitory CD33-related sialic acid-binding immunoglobulin-like lectins (Siglecs) on immune cells has been shown to influence interactions with cancer cells, including tumor immune evasion
While Jandus et al [16] identified a subset of NK cells that express Siglec-9 and showed that engagement of Siglec-9 led to immune evasion in vitro, we found that the expression of Siglec-9 ligands on carcinoma cells can modulate the immune response mediated by myelomonocytic cells [17]
Identification of LGALS3BP as a Sialic Acid-dependent Ligand for Siglec-9 —It has been shown recently that ligands for Siglec-9 are strongly up-regulated in the extracellular matrix and on the surface of tumor cells from different carcinomas, including colorectal, prostate, non-small cell lung, breast, and ovarian cancer [16, 17]

Summary

Background

Engagement of inhibitory CD33-related Siglecs on immune cells has been shown to influence interactions with cancer cells, including tumor immune evasion. LGALS3BP was able to inhibit neutrophil activation in a sialic acid- and Siglec-dependent manner These findings suggest a novel immunoinhibitory function for LGALS3BP that might be important for immune evasion of tumor cells during cancer progression. Rapid evolution of CD33rSiglecs occurs via multiple genetic mechanisms and is apparently driven by the need to maintain self-recognition by innate immune cells and by the need to escape various types of subversion by pathogens [12] Pathogens such as group B streptococci can bind to Siglec-5 and Siglec-9 on myeloid cells and inhibit the antibacterial immune response by virtue of coating themselves with sialic acid or by presenting polypeptide ligands that can bind to Siglecs [14, 15]. We propose a novel mechanism by which LGALS3BP might influence immune cell activation via Siglec engagement

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION