Abstract：
The regulated glycosylation of the proteome has widespread effects on biological processes that cancer cells can exploit. Expression of N-acetylglucosaminyltransferase V (encoded by Mgat5 or GnT-V), which catalyzes the addition of β1,6-linked N-acetylglucosamine to form complex N-glycans, has been linked to tumor growth and metastasis across tumor types. Using a panel of murine pancreatic ductal adenocarcinoma (PDAC) clonal cell lines that recapitulate the immune heterogeneity of PDAC, we found that Mgat5 is required for tumor growth in vivo but not in vitro. Loss of Mgat5 results in tumor clearance that is dependent on T cells and dendritic cells, with NK cells playing an early role. Analysis of extrinsic cell death pathways revealed Mgat5-deficient cells have increased sensitivity to cell death mediated by the TNF superfamily, a property that was shared with other non-PDAC Mgat5-deficient cell lines. Finally, Mgat5 knockout in an immunotherapy-resistant PDAC line significantly decreased tumor growth and increased survival upon immune checkpoint blockade. These findings demonstrate a role for N-glycosylation in regulating the sensitivity of cancer cells to T cell killing through classical cell death pathways.
摘要：
蛋白质组的调节糖基化对癌细胞可以利用的生物过程具有广泛的影响。N-乙酰氨基葡萄糖转移酶V（由Mgat5或GnT-V编码）的表达，它催化添加β1,6-连接的N-乙酰葡糖胺以形成复杂的N-聚糖，与肿瘤的生长和转移有关。使用一组鼠胰腺导管腺癌（PDAC）克隆细胞系，概述了PDAC的免疫异质性，我们发现Mgat5是体内肿瘤生长所必需的，而不是体外肿瘤。Mgat5的缺失导致依赖于T细胞和树突状细胞的肿瘤清除,NK细胞在早期发挥作用。外源性细胞死亡途径的分析显示，缺乏Mgat5的细胞对TNF超家族介导的细胞死亡的敏感性增加，与其他非PDACMgat5缺陷细胞系共有的特性。最后,免疫疗法抗性PDAC细胞系中的Mgat5敲除显著降低了肿瘤生长并增加了免疫检查点阻断后的存活率。这些发现证明了N-糖基化在通过经典细胞死亡途径调节癌细胞对T细胞杀伤的敏感性中的作用。
