期刊
MOLECULAR CELL
卷 81, 期 11, 页码 2317-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2021.03.037
关键词
-
资金
- NIH [R01CA177910, R35CA253027, 1K99CA259329, P50CA101942, P50CA206963]
The ketogenic diet-induced changes in energy status were found to enhance the efficacy of anti-CTLA-4 immunotherapy through various mechanisms, such as decreasing PD-L1 protein levels and increasing expression of IFNs and antigen presentation genes. AMPK activation plays a crucial role in these mechanisms, highlighting its importance in regulating the immune response to immune checkpoint blockade.
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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