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.
Keywords:
AMPK; CMTM4; CTLA-4; EZH2; PD-L1; energy stress; glucose; immune checkpoint; ketogenic diet; phosphorylation.
Copyright © 2021 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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AMP-Activated Protein Kinases / genetics*
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AMP-Activated Protein Kinases / immunology
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Allografts
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Animals
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Antibodies, Neutralizing / pharmacology
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Antineoplastic Agents / pharmacology
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B7-H1 Antigen / genetics*
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B7-H1 Antigen / immunology
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Biphenyl Compounds / pharmacology
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Breast Neoplasms / genetics*
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Breast Neoplasms / immunology
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Breast Neoplasms / mortality
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Breast Neoplasms / therapy
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CTLA-4 Antigen / antagonists & inhibitors
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CTLA-4 Antigen / genetics*
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CTLA-4 Antigen / immunology
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Cell Line, Tumor
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / immunology
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Colorectal Neoplasms / mortality
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Colorectal Neoplasms / therapy
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Diet, Ketogenic / methods
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Energy Metabolism / drug effects
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Energy Metabolism / genetics
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Enhancer of Zeste Homolog 2 Protein / genetics
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Enhancer of Zeste Homolog 2 Protein / immunology
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Immune Checkpoint Inhibitors*
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Immunotherapy / methods
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MARVEL Domain-Containing Proteins / genetics
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MARVEL Domain-Containing Proteins / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Nude
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Pyrones / pharmacology
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Signal Transduction
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Survival Analysis
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Thiophenes / pharmacology
Substances
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Antibodies, Neutralizing
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Antineoplastic Agents
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B7-H1 Antigen
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Biphenyl Compounds
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CMTM4 protein, mouse
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CTLA-4 Antigen
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Cd274 protein, mouse
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Ctla4 protein, mouse
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Immune Checkpoint Inhibitors
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MARVEL Domain-Containing Proteins
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Pyrones
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Thiophenes
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Enhancer of Zeste Homolog 2 Protein
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Ezh2 protein, mouse
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AMPK alpha1 subunit, mouse
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AMP-Activated Protein Kinases
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4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile