Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade

Xiaoming Dai, Xia Bu, Yang Gao, Jianping Guo, Jia Hu, Cong Jiang, Zhao Zhang, Kexin Xu, Jinzhi Duan, Shaohui He, Jinfang Zhang, Lixin Wan, Tianjie Liu, Xiaobo Zhou, Mien Chie Hung, Gordon J. Freeman, Wenyi Wei

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant energy status contributes to multiple metabolic diseases, including obesity, diabetes, and cancer, but the underlying mechanism remains elusive. Here, we report that ketogenic-diet-induced changes in energy status enhance the efficacy of anti-CTLA-4 immunotherapy by decreasing PD-L1 protein levels and increasing expression of type-I interferon (IFN) and antigen presentation genes. Mechanistically, energy deprivation activates AMP-activated protein kinase (AMPK), which in turn, phosphorylates PD-L1 on Ser283, thereby disrupting its interaction with CMTM4 and subsequently triggering PD-L1 degradation. In addition, AMPK phosphorylates EZH2, which disrupts PRC2 function, leading to enhanced IFNs and antigen presentation gene expression. Through these mechanisms, AMPK agonists or ketogenic diets enhance the efficacy of anti-CTLA-4 immunotherapy and improve the overall survival rate in syngeneic mouse tumor models. Our findings reveal a pivotal role for AMPK in regulating the immune response to immune-checkpoint blockade and advocate for combining ketogenic diets or AMPK agonists with anti-CTLA4 immunotherapy to combat cancer.

Original languageEnglish (US)
Pages (from-to)2317-2331.e6
JournalMolecular Cell
Volume81
Issue number11
DOIs
StatePublished - Jun 3 2021

Keywords

  • AMPK
  • CMTM4
  • CTLA-4
  • energy stress
  • EZH2
  • glucose
  • immune checkpoint
  • ketogenic diet
  • PD-L1
  • phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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