Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of I?Ba
Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of I?Ba
复制标题
有氧糖酵解通过己糖激酶 2 介导的 IγBα 磷酸化促进肿瘤免疫逃避
DOI：
10.1016/j.cmet.2022.08.002
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发表时间：
2022-09-06
期刊：
影响因子：
29
通讯作者：
Lu, Zhimin
中科院分区：
文献类型：
--
作者：
Guo, Dong;Tong, Yingying;Lu, Zhimin
PD-L1在肿瘤细胞中的高表达有助于肿瘤免疫逃避。然而，肿瘤细胞中的PD-L1表达是否受营养物质的可用性调节尚不清楚。在这里，我们发现在人胶质母细胞瘤细胞中，高葡萄糖促进己糖激酶（HK）2从线粒体上解离，以及随后的结合和T291处IkB α的磷酸化。这导致IkB α和m-钙蛋白酶蛋白酶之间的相互作用增加，随后m-钙蛋白酶介导的IkB α降解和NF-κ B激活依赖性的PD-L1表达转录上调。胶质母细胞瘤细胞中IkB α T291 A的表达阻断了高糖诱导的PD-L1表达，并促进了CD 8 + T细胞活化和浸润到肿瘤组织中，从而减少了脑肿瘤的生长。HK抑制剂和抗PD-1抗体的联合治疗消除了肿瘤免疫逃避，并显著增强了免疫检查点阻断的抗肿瘤作用。这些发现阐明了有氧糖酵解介导的PD-L1表达上调的新机制，并强调了HK 2作为葡萄糖传感器和蛋白激酶在调节肿瘤免疫逃避中的作用。
High expression of PD-L1 in tumor cells contributes to tumor immune evasion. However, whether PD-L1 expression in tumor cells is regulated by the availability of nutrients is unknown. Here, we show that in human glioblastoma cells, high glucose promotes hexokinase (HK) 2 dissociation from mitochondria and its subse-quent binding and phosphorylation of IkB alpha at T291. This leads to increased interaction between IkB alpha and m-calpain protease and subsequent m-calpain-mediated IkB alpha degradation and NF-kB activation-dependent transcriptional upregulation of PD-L1 expression. Expression of IkB alpha T291A in glioblastoma cells blocked high glucose-induced PD-L1 expression and promoted CD8+ T cell activation and infiltration into the tumor tissue, reducing brain tumor growth. Combined treatment with an HK inhibitor and an anti-PD-1 antibody eliminates tumor immune evasion and remarkably enhances the anti-tumor effect of immune checkpoint blockade. These findings elucidate a novel mechanism underlying the upregulation of PD-L1 expression mediated by aerobic glycolysis and underscore the roles of HK2 as a glucose sensor and a protein kinase in regulation of tumor immune evasion.