浙江大学医学院Zhimin Lu团队近期取得重要工作进展，他们研究发现有氧糖酵解通过己糖酶2介导的IκBα的磷酸化促进肿瘤免疫逃逸。相关工作2022年8月24日在线发表于《细胞—代谢》杂志上。

研究人员发现，在人类胶质母细胞瘤细胞中，高葡萄糖促进己糖激酶（HK）2从线粒体中解离，随后与IκBα在T291处结合并使其磷酸化。这导致IκBα和μ-calpain蛋白酶之间的相互作用增加，以及随后μ-calpain蛋白酶介导的IκBα降解和NF-κB激活依赖的PD-L1表达上调。IκBα T291A在胶质母细胞瘤细胞中的表达阻断了高糖诱导的PD-L1表达，促进了CD8+ 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逸，显著增强了免疫检查点阻断的抗肿瘤作用。这些发现阐明了由有氧糖酵解介导的PD-L1表达上调的新机制，并强调了HK2作为葡萄糖传感器和蛋白激酶在调节肿瘤免疫逃逸中的作用。

据介绍，PD-L1在肿瘤细胞中的高表达有助于肿瘤免疫逃逸。然而，PD-L1在肿瘤细胞中的表达是否受到营养物质的调节尚不清楚。

附：英文原文

Title: Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα

Author: Dong Guo, Yingying Tong, Xiaoming Jiang, Ying Meng, Hongfei Jiang, Linyong Du, Qingang Wu, Shan Li, Shudi Luo, Min Li, Liwei Xiao, Haiyan He, Xuxiao He, Qiujing Yu, Jing Fang, Zhimin Lu

Issue&Volume: 2022-08-24

Abstract: 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 nutrientsis unknown. Here, we show that in human glioblastoma cells, high glucose promoteshexokinase (HK) 2 dissociation from mitochondria and its subsequent binding and phosphorylationof IκBα at T291. This leads to increased interaction between IκBα and μ-calpain proteaseand subsequent μ-calpain-mediated IκBα degradation and NF-κB activation-dependenttranscriptional upregulation of PD-L1 expression. Expression of IκBα T291A in glioblastomacells 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 tumorimmune evasion and remarkably enhances the anti-tumor effect of immune checkpointblockade. These findings elucidate a novel mechanism underlying the upregulation ofPD-L1 expression mediated by aerobic glycolysis and underscore the roles of HK2 asa glucose sensor and a protein kinase in regulation of tumor immune evasion.

DOI: 10.1016/j.cmet.2022.08.002

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00345-X