While recent research points to the importance of glycans in cancer immunity, knowledge on functional mechanisms is lacking. In lung carcinoma among other tumors, anti-tumor immunity is suppressed; and while some recent therapies boost T-cell mediated immunity by targeting immune-checkpoint pathways, robust responses are uncommon. Augmenting tumor antigen-specific immune responses by endogenous dendritic cells (DCs) is appealing from a specificity standpoint, but challenging. Here, we show that restricting a heparan sulfate (HS) loss-of-function mutation in the HS sulfating enzyme Ndst1 to predominantly conventional DCs (Ndst1f/f CD11cCre+ mutation) results in marked inhibition of Lewis lung carcinoma growth along with increased tumor-associated CD8+ T cells. In mice deficient in a major DC HS proteoglycan (syndecan-4), splenic CD8+ T cells showed increased anti-tumor cytotoxic responses relative to controls. Studies examining Ndst1f/f CD11cCre + mutants revealed that mutation was associated with an increase in anti-tumor cytolysis using either splenic CD8+ T cells or tumor-infiltrating (TIL) CD8+ T cells purified ex-vivo, and tested in pooled effector-to-target cytolytic assays against tumor cells from respective animals. On glycan compositional analysis, HS purified from Ndst1f/f CD11cCre + mutant DCs had reduced overall sulfation, including reduced sulfation of a tri-sulfated disaccharide species that was intriguingly abundant on wildtype DC HS. Interestingly, antigen presentation in the context of major histocompatibility complex class-I (MHC-I) was enhanced in mutant DCs, with more striking effects in the setting of HS under-sulfation, pointing to a likely regulatory role by sulfated glycans at the antigen/MHC-I - T-cell interface; and possibly future opportunities to improve antigen-specific T cell responses by immunologic targeting of HS proteoglycans in cancer.

中文翻译：

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功能性细胞抗肿瘤机制通过基因蛋白聚糖靶向增强。

尽管最近的研究指出聚糖在癌症免疫中的重要性，但缺乏有关功能机制的知识。在肺癌以及其他肿瘤中，抗肿瘤免疫力受到抑制；虽然最近的一些疗法通过靶向免疫检查点途径来增强T细胞介导的免疫力，但强烈的反应并不常见。从特异性的观点来看，内源性树突状细胞（DC）增强肿瘤抗原特异性免疫反应是有吸引力的，但具有挑战性。在这里，我们显示出将HS硫酸化酶Ndst1中的硫酸乙酰肝素（HS）功能丧失突变限制为主要常规DC（Ndst1f / f CD11cCre +突变）会导致对Lewis肺癌生长的明显抑制以及与肿瘤相关的增加CD8 + T细胞。在缺乏主要DC HS蛋白聚糖（syndecan-4）的小鼠中，相对于对照，脾CD8 + T细胞显示出增加的抗肿瘤细胞毒性反应。研究Ndst1f / f CD11cCre +突变体的研究表明，该突变与使用脾CD8 + T细胞或离体纯化的肿瘤浸润（TIL）CD8 + T细胞的抗肿瘤细胞溶解增加有关，并在汇集的效应子对靶向针对来自各个动物的肿瘤细胞的细胞溶解测定。在聚糖成分分析中，从Ndst1f / f CD11cCre +突变DC纯化得到的HS减少了总体硫酸盐化，包括减少了在野生型DC HS上大量存在的三硫酸化二糖物种的硫酸盐化。有趣的是，在突变型DC中，主要组织相容性复合物I类（MHC-I）背景下的抗原呈递得到了增强，在HS硫酸盐不足的情况下具有更显着的作用，指出硫酸化聚糖可能在抗原/ MHC-1-T细胞界面上起调节作用；以及通过免疫靶向HS蛋白多糖在癌症中改善抗原特异性T细胞反应的未来机会。