Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade.
Mol Cell
; 81(11): 2317-2331.e6, 2021 06 03.
Article
in En
| MEDLINE
| ID: mdl-33909988
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Breast Neoplasms
/
Colorectal Neoplasms
/
AMP-Activated Protein Kinases
/
B7-H1 Antigen
/
CTLA-4 Antigen
/
Immune Checkpoint Inhibitors
Type of study:
Prognostic_studies
Language:
En
Journal:
Mol Cell
Journal subject:
BIOLOGIA MOLECULAR
Year:
2021
Type:
Article
Affiliation country:
United States