PDF(Pubmed)
Abstract：
BACKGROUND: Enhanced glucose metabolism has been reported in many cancers. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme involved in the pentose phosphate pathway, which maintains NADPH levels and protects cells from oxidative damage. We recently found that low G6PD expression correlates with active tumor immunity. However, the mechanism involving G6PD and tumor immunity remained unclear.
METHODS: We conducted in vitro studies using G6PD-knocked down malignant melanoma cells, pathway analysis using the GEO dataset, in vivo studies in combination with immune checkpoint inhibitors (ICIs) using a mouse melanoma model, and prognostic analysis in 42 melanoma patients and 30 lung cancer patients who were treated with ICIs.
RESULTS: Inhibition of G6PD, both chemically and genetically, has been shown to decrease the production of NADPH and reduce their oxidative stress tolerance. This leads to cell death, which is accompanied by the release of high mobility group box 1 and the translocation of calreticulin to the plasma membrane. These findings suggested that inhibiting G6PD can induce immunogenic cell death. In experiments with C57BL/6 mice transplanted with G6PD-knockdown B16 melanoma cells and treated with anti-PD-L1 antibody, a significant reduction in tumor size was observed. Interestingly, inhibiting G6PD in only a part of the lesions increased the sensitivity of other lesions to ICI. Additionally, out of 42 melanoma patients and 30 lung cancer patients treated with ICIs, those with low G6PD expression had a better prognosis than those with high G6PD expression (p=0.0473; melanoma, p=0.0287; lung cancer).
CONCLUSIONS: G6PD inhibition is a potent therapeutic strategy that triggers immunogenic cell death in tumors, significantly augmenting the efficacy of immunotherapies.
METHODS: We conducted in vitro studies using G6PD-knocked down malignant melanoma cells, pathway analysis using the GEO dataset, in vivo studies in combination with immune checkpoint inhibitors (ICIs) using a mouse melanoma model, and prognostic analysis in 42 melanoma patients and 30 lung cancer patients who were treated with ICIs.
RESULTS: Inhibition of G6PD, both chemically and genetically, has been shown to decrease the production of NADPH and reduce their oxidative stress tolerance. This leads to cell death, which is accompanied by the release of high mobility group box 1 and the translocation of calreticulin to the plasma membrane. These findings suggested that inhibiting G6PD can induce immunogenic cell death. In experiments with C57BL/6 mice transplanted with G6PD-knockdown B16 melanoma cells and treated with anti-PD-L1 antibody, a significant reduction in tumor size was observed. Interestingly, inhibiting G6PD in only a part of the lesions increased the sensitivity of other lesions to ICI. Additionally, out of 42 melanoma patients and 30 lung cancer patients treated with ICIs, those with low G6PD expression had a better prognosis than those with high G6PD expression (p=0.0473; melanoma, p=0.0287; lung cancer).
CONCLUSIONS: G6PD inhibition is a potent therapeutic strategy that triggers immunogenic cell death in tumors, significantly augmenting the efficacy of immunotherapies.
摘要：
背景：已经在许多癌症中报道了增强的葡萄糖代谢。葡萄糖-6-磷酸脱氢酶（G6PD）是参与戊糖磷酸途径的限速酶，维持NADPH水平并保护细胞免受氧化损伤。我们最近发现低G6PD表达与活跃的肿瘤免疫相关。然而,涉及G6PD和肿瘤免疫的机制尚不清楚。
方法：我们使用G6PD敲低恶性黑色素瘤细胞进行了体外研究，使用GEO数据集进行路径分析，使用小鼠黑色素瘤模型与免疫检查点抑制剂（ICIs）结合进行体内研究，42例黑色素瘤患者和30例接受ICIs治疗的肺癌患者的预后分析。
结果：抑制G6PD，化学和遗传，已被证明可以减少NADPH的产生并降低其氧化应激耐受性。这导致细胞死亡,伴随着高迁移率基团盒1的释放和钙网蛋白向质膜的易位。这些发现表明抑制G6PD可以诱导免疫原性细胞死亡。在C57BL/6小鼠移植G6PD敲低B16黑素瘤细胞并用抗PD-L1抗体处理的实验中，观察到肿瘤大小显著减小.有趣的是,仅在部分病变中抑制G6PD增加了其他病变对ICI的敏感性。此外,在接受ICIs治疗的42例黑色素瘤患者和30例肺癌患者中，G6PD低表达者比G6PD高表达者预后更好(p=0.0473;黑色素瘤,p=0.0287；肺癌）。
结论：G6PD抑制是一种有效的治疗策略，可引发肿瘤中的免疫原性细胞死亡，显着增强免疫疗法的功效。
方法：我们使用G6PD敲低恶性黑色素瘤细胞进行了体外研究，使用GEO数据集进行路径分析，使用小鼠黑色素瘤模型与免疫检查点抑制剂（ICIs）结合进行体内研究，42例黑色素瘤患者和30例接受ICIs治疗的肺癌患者的预后分析。
结果：抑制G6PD，化学和遗传，已被证明可以减少NADPH的产生并降低其氧化应激耐受性。这导致细胞死亡,伴随着高迁移率基团盒1的释放和钙网蛋白向质膜的易位。这些发现表明抑制G6PD可以诱导免疫原性细胞死亡。在C57BL/6小鼠移植G6PD敲低B16黑素瘤细胞并用抗PD-L1抗体处理的实验中，观察到肿瘤大小显著减小.有趣的是,仅在部分病变中抑制G6PD增加了其他病变对ICI的敏感性。此外,在接受ICIs治疗的42例黑色素瘤患者和30例肺癌患者中，G6PD低表达者比G6PD高表达者预后更好(p=0.0473;黑色素瘤,p=0.0287；肺癌）。
结论：G6PD抑制是一种有效的治疗策略，可引发肿瘤中的免疫原性细胞死亡，显着增强免疫疗法的功效。
