Fructose-1,6-bisphosphatase loss modulates STAT3-dependent expression of PD-L1 and cancer immunity.
果糖-1,6-双磷酸酶损失调节 STAT3-dependent PD-L1 和癌症免疫的表达。
FBP1 PD-L1 STAT3 cancer immunity checkpoint blockade therapy
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摘要

Rationale: Abnormal expression of programmed death-1 (PD-1) ligand-1(PD-L1) in cancer cells plays a crucial role in cancer immune evasion and progression. The immune checkpoint molecules PD-1 and PD-L1 have been targeted for cancer treatment with significant benefits for cancer patients. However, the response rate is relatively low in certain types of cancer and the underlying mechanism remains poorly understood. Better understanding of the molecular mechanism of PD-L1 expression regulation in cancer cells is urgently needed to improve the treatment response rate and overall survival of patients. Fructose-1, 6-biphosphatase (FBP1) is a key enzyme in gluconeogenesis and is implicated in human cancer due to its frequent loss in various cancer types. Methods: Expression of FBP1 and PD-L1 was analyzed in various cancer cell lines. Western blot and RT-qPCR were performed to determine whether FBP1 regulates PD-L1 expression. Co-immunoprecipitation and glutathione S-transferase (GST) pulldown assay were employed to define the underlying regulatory mechanisms. Immunohistochemistry was conducted to determine the correlation between FBP1 and PD-L1 expression in a cohort of patients. A cancer syngeneic mouse model was utilized to examine how FBP1 affects tumor immunity. Results: We demonstrated that in a manner independent of its enzymatic activity FBP1 downregulates the expression of PD-L1 in various cell lines of different cancer types including pancreatic and prostate cancer. We further showed that this regulation occurs at the transcriptional level and is mediated by FBP1 inhibition of signal transducer and activator of transcription-3 (STAT3)-dependent PD-L1 transcription. Moreover, FBP1 and PD-L1 protein expression were negatively correlated in pancreatic ductal adenocarcinoma (PDAC) specimens from a cohort of patients. Most importantly, we demonstrated that decreased FBP1 expression promotes tumor growth and resistance to immune checkpoint blockade therapy in mice. Conclusions: Our findings reveal a new tumor suppressor function of FBP1 in inhibiting PD-L1 expression and enhancing cancer immunity. They also suggest that FBP1-deficient human cancers could be therapeutically targeted by PD-1/PD-L1-based immune checkpoint blockade therapy.

译文

原理: 程序性死亡-1 (PD-1) ligand-1 (PD-L1) 在癌细胞中的异常表达在癌症免疫逃避和进展中起着至关重要的作用。PD-1 和 PD-L1 的免疫检查点分子已经成为癌症治疗的目标,对癌症患者有显著的益处。然而,某些类型的癌症的反应率相对较低,其潜在机制仍然知之甚少。迫切需要更好地理解癌细胞中 PD-L1 表达调控的分子机制,以提高治疗反应率和患者的整体存活率。果糖-1,6-二磷酸酶 (FBP1) 是糖异生过程中的一种关键酶,由于其在各种癌症类型中的频繁丢失,与人类癌症有关。方法: 分析 FBP1 和 PD-L1 在各种癌细胞系中的表达。进行 Western 印迹和 RT-qPCR 以确定 FBP1 是否调控 PD-L1 的表达。共免疫沉淀和谷胱甘肽 S-转移酶 (GST) 下拉试验被用来定义潜在的调控机制。进行免疫组织化学检测以确定 FBP1 和 PD-L1 在患者队列中的表达之间的相关性。使用癌症同系小鼠模型来检查 FBP1 如何影响肿瘤免疫。结果: 我们证明了 FBP1 以一种独立于其酶活性的方式下调了包括胰腺癌和前列腺癌在内的不同癌症类型的各种细胞系中 PD-L1 的表达。我们进一步表明,这种调控发生在转录水平,并由 FBP1 抑制信号转导子和转录激活子-3 (stat 3) 依赖性 PD-L1 转录介导。此外,来自队列患者的胰腺导管腺癌 (PDAC) 标本中 FBP1 和 PD-L1 蛋白表达呈负相关。最重要的是,我们证明了在小鼠中降低 FBP1 表达促进肿瘤生长和对免疫检查点阻断疗法的抵抗。结论: 我们的发现揭示了 FBP1 在抑制 PD-L1 表达和增强癌症免疫方面的一种新的肿瘤抑制功能。他们还建议 FBP1-deficient 人类癌症可以通过 PD-1/PD-L1-based 免疫检查点阻断疗法进行治疗。

Fructose

内分泌 单糖 临床研究术语
概述  :  

果糖是一个简单的单糖,它在消化过程中会被直接吸收到血液中。纯净的干果糖是一种白色,无味的结晶固体,是所有糖中水溶性最高的。果糖存在于蜂蜜,树木和藤本植物的水果,花朵,浆果和大多数根茎类蔬菜中。 食物来源 果糖的天然来源包括水果,蔬菜(包括甘蔗)和蜂蜜。果糖通常从这些来源进一步浓缩。除了纯结晶果糖以外,果糖的最高饮食来源是含食用糖(蔗糖),高果糖玉米糖浆,龙舌兰花蜜,蜂蜜,糖蜜,枫糖浆,水果和果汁的食物,因为这些食物中果糖的比例

fructose   英 /ˈfrʌktəʊs; ˈfrʌktəʊz/   美 /ˈfrʌktoʊs,ˈfrʌktoʊz/

释    义   n. [有化] 果糖;左旋糖

例    句   You should also avoid beverages with added sugars such as high-fructose corn syrup.你还应该避免含有像高果糖玉米糖浆这样的添加糖的饮料。

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