Lectin Galactoside-binding Soluble 3 Binding Protein (LGALS3BP) Is a Tumor-associated Immunomodulatory Ligand for CD33-related Siglecs
Lectin Galactoside-binding Soluble 3 Binding Protein (LGALS3BP) Is a Tumor-associated Immunomodulatory Ligand for CD33-related Siglecs
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DOI：
10.1074/jbc.m114.593129
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发表时间：
2014-11-28
影响因子：
4.8
通讯作者：
Varki, Ajit
中科院分区：
文献类型：
--
作者：
Laeubli, Heinz;Alisson-Silva, Frederico;Varki, Ajit
凝集素半乳糖苷结合可溶性3结合蛋白（LGALS 3BP，也称为Mac-2结合蛋白）是一种高度糖基化的分泌分子，先前已显示其在许多癌症中上调，并与肿瘤转移过程以及其他细胞粘附和免疫功能有关。唾液酸结合免疫球蛋白样凝集素（Siglecs）的CD 33相关亚类由免疫调节分子组成，这些分子最近与癌症免疫应答的调节相关。由于已经观察到Siglec配体在癌症组织中的上调，因此这些与抑制性CD 33相关Siglec结合的癌症相关配体的表征可以为癌症免疫调节治疗提供新的靶标。在这里，我们使用肿瘤细胞提取物的亲和色谱法来鉴定LGALS 3BP作为人Siglec-9和其他免疫调节性Siglec（如Siglec-5和Siglec-10）的新型唾液酸依赖性配体。相比之下，小鼠同源物Siglec-E以较低的亲和力结合鼠LGALS 3BP。已观察到LGALS 3BP在人结直肠癌和前列腺癌标本中上调，特别是在细胞外基质中。最后，LGALS 3BP能够以唾液酸和Siglec依赖性方式抑制中性粒细胞活化。这些发现表明LGALS 3BP的一种新的免疫抑制功能，可能对癌症进展期间肿瘤细胞的免疫逃避很重要。
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.