2. Academic Validation
  3. Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα

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

  • Cell Metab. 2022 Sep 6;34(9):1312-1324.e6. doi: 10.1016/j.cmet.2022.08.002.
Dong Guo 1,  Yingying Tong 2,  Xiaoming Jiang 1,  Ying Meng 1,  Hongfei Jiang 3,  Linyong Du 4,  Qingang Wu 1,  Shan Li 1,  Shudi Luo 1,  Min Li 1,  Liwei Xiao 1,  Haiyan He 1,  Xuxiao He 1,  Qiujing Yu 5,  Jing Fang 3,  Zhimin Lu 6
Affiliations

Affiliations

  • 1 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China.
  • 2 Cancer Center, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China.
  • 3 The Affiliated Hospital of Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China.
  • 4 Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 5 Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 6 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China. Electronic address: [email protected].
PMID: 36007522 DOI: 10.1016/j.cmet.2022.08.002
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 nutrients is unknown. Here, we show that in human glioblastoma cells, high glucose promotes Hexokinase (HK) 2 dissociation from mitochondria and its subsequent binding and phosphorylation of IκBα at T291. This leads to increased interaction between IκBα and μ-calpain protease and subsequent μ-calpain-mediated IκBα degradation and NF-κB activation-dependent transcriptional upregulation of PD-L1 expression. Expression of IκBα 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.

Keywords

HK2; IκBα; NF-κB; PD-L1; glycolysis; immune evasion; phosphorylation; protein kinase.

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