Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade
2021
Dai, Xiaoming | Bu, Xia | Gao, Yang | Guo, Jianping | Hu, Jia | Jiang, Cong | Zhang, Zhao | Xu, Kexin | Duan, Jinzhi | He, Shaohui | Zhang, Jinfang | Wan, Lixin | Liu, Tianjie | Zhou, Xiaobo | Hung, Mien-chie | Freeman, Gordon J. | Wei, Wenyi
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.
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