| First Author | Dai X | Year | 2021 |
| Journal | Mol Cell | Volume | 81 |
| Issue | 11 | Pages | 2317-2331.e6 |
| PubMed ID | 33909988 | Mgi Jnum | J:307170 |
| Mgi Id | MGI:6718912 | Doi | 10.1016/j.molcel.2021.03.037 |
| Citation | Dai X, et al. (2021) Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade. Mol Cell 81(11):2317-2331.e6 |
| abstractText | 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. |
