BACKGROUND We investigated the role of PD-L1 in the metabolic reprogramming of non-small cell lung cancer (NSCLC). METHODS Changes in glycolysis-related molecules and glycolytic activity were evaluated in PD-L1low and PD-L1high NSCLC cells after transfection or knockdown of PD-L1, respectively. Jurkat T-cell activation was assessed after co-culture with NSCLC cells. The association between PD-L1 and immune response-related molecules or glycolysis were analyzed in patients with NSCLC and The Cancer Genome Atlas (TCGA). RESULTS Transfecting PD-L1 in PD-L1low cells enhanced hexokinase-2 (HK2) expression, lactate production, and extracellular acidification rates, but minimally altered GLUT1 and PKM2 expression and oxygen consumption rates. By contrast, knocking-down PD-L1 in PD-L1high cells decreased HK2 expression and glycolysis by suppressing PI3K/Akt and Erk pathways. Interferon-γ (IFNγ) secretion and activation marker expression was decreased in stimulated Jurkat T-cells when co-cultured with HK2-overexpressing vector-transfected tumor cells rather than empty vector-transfected tumor cells. Immunohistochemistry revealed that PD-L1 expression was positively correlated with HK2 expression in NSCLC (p < 0.001). In TCGA, HK2 exhibited a positive linear association with CD274 (PD-L1) expression (p < 0.001) but an inverse correlation with the expression of CD4, CD8A, and T-cell effector function-related genes in the CD274high rather than CD274low group. Consistently, there were fewer CD8+ T-cells in PD-L1positive/HK2high tumors compared to PD-L1positive/HK2low tumors in squamous cell carcinoma. CONCLUSIONS PD-L1 enhances glycolysis in NSCLC by upregulating HK2, which might dampen anti-tumor immunity. PD-L1 may contribute to NSCLC oncogenesis by inducing metabolic reprogramming and immune checkpoint.

中文翻译：

---

非小细胞肺癌中编程性细胞死亡配体1介导的己糖激酶2表达增强与T细胞效应子基因表达成反比。

背景我们研究了PD-L1在非小细胞肺癌（NSCLC）的代谢重编程中的作用。方法分别评估PD-L1low和PD-L1high NSCLC细胞转染或敲低PD-L1后糖酵解相关分子的变化和糖酵解活性。与NSCLC细胞共培养后，评估Jurkat T细胞活化。在NSCLC和癌症基因组图谱（TCGA）患者中分析了PD-L1与免疫反应相关分子或糖酵解之间的关联。结果在PD-L1low细胞中转染PD-L1可增强己糖激酶2（HK2）的表达，乳酸的产生和细胞外酸化率，但对GLUT1和PKM2的表达及耗氧率的影响却很小。相比之下，抑制PD-L1高细胞中的PD-L1可以通过抑制PI3K / Akt和Erk途径降低HK2表达和糖酵解。与过表达HK2的载体转染的肿瘤细胞（而不是空载体转染的肿瘤细胞）共培养时，刺激的Jurkat T细胞中干扰素-γ（IFNγ）的分泌和激活标记物表达降低。免疫组化显示NSCLC中PD-L1表达与HK2表达呈正相关（p <0.001）。在TCGA中，HK2与CD274（PD-L1）表达呈线性正相关（p <0.001），但与CD274high而非CD274low组中CD4，CD8A和T细胞效应子功能相关基因的表达呈负相关。 。始终如一 与鳞状细胞癌的PD-L1阳性/ HK2低肿瘤相比，PD-L1阳性/ HK2高肿瘤中CD8 + T细胞更少。结论PD-L1通过上调HK2增强NSCLC的糖酵解作用，这可能削弱抗肿瘤免疫力。PD-L1可能通过诱导代谢重编程和免疫检查点来促进NSCLC的发生。