PMID- 36007522
OWN - NLM
STAT- MEDLINE
DCOM- 20220909
LR  - 20221005
IS  - 1932-7420 (Electronic)
IS  - 1550-4131 (Linking)
VI  - 34
IP  - 9
DP  - 2022 Sep 6
TI  - Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated 
      phosphorylation of IkappaBalpha.
PG  - 1312-1324.e6
LID - S1550-4131(22)00345-X [pii]
LID - 10.1016/j.cmet.2022.08.002 [doi]
AB  - 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 IkappaBalpha at T291. This leads to increased 
      interaction between IkappaBalpha and mu-calpain protease and subsequent mu-calpain-mediated 
      IkappaBalpha degradation and NF-kappaB activation-dependent transcriptional upregulation of 
      PD-L1 expression. Expression of IkappaBalpha 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.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Guo, Dong
AU  - Guo D
AD  - 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.
FAU - Tong, Yingying
AU  - Tong Y
AD  - Cancer Center, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, 
      China.
FAU - Jiang, Xiaoming
AU  - Jiang X
AD  - 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.
FAU - Meng, Ying
AU  - Meng Y
AD  - 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.
FAU - Jiang, Hongfei
AU  - Jiang H
AD  - The Affiliated Hospital of Qingdao University, Qingdao Cancer Institute, Qingdao, 
      Shandong 266071, China.
FAU - Du, Linyong
AU  - Du L
AD  - Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of 
      Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, 
      Zhejiang 325035, China.
FAU - Wu, Qingang
AU  - Wu Q
AD  - 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.
FAU - Li, Shan
AU  - Li S
AD  - 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.
FAU - Luo, Shudi
AU  - Luo S
AD  - 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.
FAU - Li, Min
AU  - Li M
AD  - 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.
FAU - Xiao, Liwei
AU  - Xiao L
AD  - 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.
FAU - He, Haiyan
AU  - He H
AD  - 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.
FAU - He, Xuxiao
AU  - He X
AD  - 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.
FAU - Yu, Qiujing
AU  - Yu Q
AD  - Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), 
      Department of Immunology, School of Basic Medical Sciences, Tianjin Medical 
      University, Tianjin 300070, China.
FAU - Fang, Jing
AU  - Fang J
AD  - The Affiliated Hospital of Qingdao University, Qingdao Cancer Institute, Qingdao, 
      Shandong 266071, China.
FAU - Lu, Zhimin
AU  - Lu Z
AD  - 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: zhiminlu@zju.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220824
PL  - United States
TA  - Cell Metab
JT  - Cell metabolism
JID - 101233170
RN  - 0 (B7-H1 Antigen)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - *B7-H1 Antigen
MH  - Cell Line, Tumor
MH  - *Glioblastoma
MH  - Glucose
MH  - Glycolysis
MH  - Humans
MH  - NF-KappaB Inhibitor alpha/metabolism
MH  - Phosphorylation
MH  - Tumor Escape
OTO - NOTNLM
OT  - HK2
OT  - IkappaBalpha
OT  - NF-kappaB
OT  - PD-L1
OT  - glycolysis
OT  - immune evasion
OT  - phosphorylation
OT  - protein kinase
COIS- Declaration of interests Z.L. owns shares in Signalway Biotechnology (Pearland, 
      TX), which supplied rabbit antibodies that recognize IkappaBalpha pT291. Z.L.'s interest 
      in this company had no bearing on its being chosen to supply these reagents.
EDAT- 2022/08/26 06:00
MHDA- 2022/09/11 06:00
CRDT- 2022/08/25 18:42
PHST- 2021/12/22 00:00 [received]
PHST- 2022/05/25 00:00 [revised]
PHST- 2022/08/03 00:00 [accepted]
PHST- 2022/08/26 06:00 [pubmed]
PHST- 2022/09/11 06:00 [medline]
PHST- 2022/08/25 18:42 [entrez]
AID - S1550-4131(22)00345-X [pii]
AID - 10.1016/j.cmet.2022.08.002 [doi]
PST - ppublish
SO  - Cell Metab. 2022 Sep 6;34(9):1312-1324.e6. doi: 10.1016/j.cmet.2022.08.002. Epub 
      2022 Aug 24.