Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth.
Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth.
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DOI：
10.1016/j.neo.2016.04.004
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Fuster MM
中科院分区：
文献类型：
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作者：
El Ghazal R;Yin X;Johns SC;Swanson L;Macal M;Ghosh P;Zuniga EI;Fuster MM
在癌症中，蛋白多糖被发现在促进生长因子的作用以及影响基质侵袭和重塑方面发挥作用。然而，关于树突状细胞(DC)上蛋白多糖所显示的糖链在肿瘤免疫中的遗传和功能重要性，人们知之甚少。在肺癌等实体瘤中，肿瘤相关树突状细胞在很大程度上发挥着颠覆/抑制作用，促进肿瘤的生长和发展。在此，我们证明了通过突变小鼠硫酸乙酰肝素生物合成酶N-脱乙酰酶/N-磺基转移酶-1(NDST1)来靶向DC糖硫化可促进DC成熟并抑制DC向引流淋巴结的运输。淋巴驱动的DC迁移和趋化因子(CCL21)依赖的DC迁移所需的主要信号通路的激活(通过磷酸化Akt测定)对DC中的NDST1突变敏感。NDST1基因缺失的小鼠Lewis肺癌肿瘤体积缩小。从肿瘤中纯化的CD11c+细胞，其中包含肿瘤浸润性DC群体，在突变细胞中显示出类似的表型。这些特征在缺乏Syndecan-4的小鼠中复制，Syndecan-4是DC表面表达的主要硫酸乙酰肝素蛋白多糖：在Syndecan-4缺陷的小鼠中，肿瘤生长受到损害，其特征是成熟DC的浸润增加。突变背景的肿瘤也表现出更多的NK细胞和NKT细胞的浸润。这些发现表明DC硫酸乙酰肝素蛋白多糖在肿瘤生长中的遗传学重要性，并可能指导针对Syndecan-4和乙酰肝素硫酸盐治疗癌症的新策略的开发。
In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs) in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1) in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21)-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt) were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c + cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4–deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer.