Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Mol Cell. 2021 Jun 3;81(11):2317-2331.e6. doi: 10.1016/j.molcel.2021.03.037. Epub 2021 Apr 27.
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.
异常的能量状态会导致多种代谢疾病，包括肥胖、糖尿病和癌症，但潜在的机制仍难以捉摸。在这里，我们报告说，生酮饮食引起的能量状态变化通过降低 PD-L1 蛋白水平和增加 I 型干扰素 (IFN) 和抗原呈递基因的表达来增强抗 CTLA-4 免疫疗法的疗效。在机制上，能量剥夺会激活 AMP 激活的蛋白激酶 (AMPK)，后者反过来磷酸化 PD-L1 上的 Ser283，从而破坏其与 CMTM4 的相互作用，并随后触发 PD-L1 降解。此外，AMPK 磷酸化 EZH2，破坏 PRC2 功能，导致 IFN 和抗原呈递基因表达增强。通过这些机制，AMPK 激动剂或生酮饮食增强了抗 CTLA-4 免疫疗法的疗效，并提高了同种异体小鼠肿瘤模型的总生存率。我们的研究结果揭示了 AMPK 在调节免疫检查点阻断的免疫反应中的关键作用，并主张将生酮饮食或 AMPK 激动剂与抗 CTLA4 免疫疗法相结合，以对抗癌症。
