The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9.
The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9.
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粘蛋白MUC1通过参与凝集素SIGLEC-9调节肿瘤免疫学微环境。
DOI：
10.1038/ni.3552
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发表时间：
2016-11
影响因子：
30.5
通讯作者：
Burchell JM
中科院分区：
文献类型：
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作者：
Beatson R;Tajadura-Ortega V;Achkova D;Picco G;Tsourouktsoglou TD;Klausing S;Hillier M;Maher J;Noll T;Crocker PR;Taylor-Papadimitriou J;Burchell JM
Siglec-9是一种唾液酸结合凝集素，主要表达于髓系细胞。基本上在所有类型的癌症中都会发生异常糖基化，导致唾液酸化增加。因此，当MUC1在癌细胞上表达时，它被多个短的、唾液酸化的O-连接多糖(MUC1-ST)装饰。在这里，我们展示了这种癌症特异性的MUC1糖形式，通过Siglec-9的参与，教育髓系细胞释放与肿瘤微环境决定和疾病进展相关的因子。MUC1ST诱导巨噬细胞呈现样表型，PD-L1表达增加。MUC1-ST与Siglec-9结合不能激活SHP-1/2，但意外地诱导钙离子通量导致MEK-ERK激活。这项工作定义了异常糖基化的MUC1的关键作用，并确定了Siglec-9参与后的激活途径。
Siglec-9 is a sialic acid binding lectin predominantly expressed on myeloid cells. Aberrant glycosylation occurs in essentially all types of cancers resulting in increased sialylation. Thus when MUC1 is expressed on cancer cells it is decorated by multiple short, sialylated O-linked glycans (MUC1-ST). Here we show that this cancer-specific MUC1 glycoform could, through the engagement of Siglec-9, educate myeloid cells to release factors associated with tumor microenvironment determination and disease progression. Moreover MUC1-ST induced macrophages to display a TAM-like phenotype with increased expression of PD-L1. MUC1-ST binding to Siglec-9 did not activate SHP-1/2 but surprisingly induced calcium flux leading to MEK-ERK activation. This work defines a critical role for aberrantly glycosylated MUC1 and identifies an activating pathway following Siglec-9 engagement.