Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade.
AMP-Activated Protein Kinases
/ genetics
Allografts
Animals
Antibodies, Neutralizing
/ pharmacology
Antineoplastic Agents
/ pharmacology
B7-H1 Antigen
/ genetics
Biphenyl Compounds
/ pharmacology
Breast Neoplasms
/ genetics
CTLA-4 Antigen
/ antagonists & inhibitors
Cell Line, Tumor
Colorectal Neoplasms
/ genetics
Diet, Ketogenic
/ methods
Energy Metabolism
/ drug effects
Enhancer of Zeste Homolog 2 Protein
/ genetics
Female
Gene Expression Regulation, Neoplastic
Humans
Immune Checkpoint Inhibitors
Immunotherapy
/ methods
MARVEL Domain-Containing Proteins
/ genetics
Mice
Mice, Inbred C57BL
Mice, Nude
Pyrones
/ pharmacology
Signal Transduction
Survival Analysis
Thiophenes
/ pharmacology
AMPK
CMTM4
CTLA-4
EZH2
PD-L1
energy stress
glucose
immune checkpoint
ketogenic diet
phosphorylation
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
03 06 2021
03 06 2021
Historique:
received:
01
04
2020
revised:
26
10
2020
accepted:
22
03
2021
pubmed:
29
4
2021
medline:
23
6
2021
entrez:
28
4
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33909988
pii: S1097-2765(21)00232-X
doi: 10.1016/j.molcel.2021.03.037
pmc: PMC8178223
mid: NIHMS1690825
pii:
doi:
Substances chimiques
Antibodies, Neutralizing
0
Antineoplastic Agents
0
B7-H1 Antigen
0
Biphenyl Compounds
0
CMTM4 protein, mouse
0
CTLA-4 Antigen
0
Cd274 protein, mouse
0
Ctla4 protein, mouse
0
Immune Checkpoint Inhibitors
0
MARVEL Domain-Containing Proteins
0
Pyrones
0
Thiophenes
0
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Ezh2 protein, mouse
EC 2.1.1.43
AMPK alpha1 subunit, mouse
EC 2.7.11.1
AMP-Activated Protein Kinases
EC 2.7.11.31
4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
P68477CD2C
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2317-2331.e6Subventions
Organisme : NCI NIH HHS
ID : K99 CA259329
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA206963
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA101942
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM094777
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA177910
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA253027
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests G.J.F. has patents/pending royalties on the PD-1 pathway from Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Dako, and Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, NextPoint, IgM, Jubilant, Geode, and GV20. G.J.F. has equity in Nextpoint, Triursus, Xios, iTeos, IgM, Geode, and GV20. W.W. is a co-founder and consultant for ReKindle Therapeutics. The other authors declare no competing interests.
Références
J Immunother Cancer. 2018 Oct 22;6(1):109
pubmed: 30348216
Nat Cell Biol. 2007 Feb;9(2):218-24
pubmed: 17237771
Mol Cell. 2013 May 9;50(3):407-19
pubmed: 23623684
Science. 2009 May 22;324(5930):1029-33
pubmed: 19460998
Trends Biochem Sci. 2018 Dec;43(12):1014-1032
pubmed: 30287140
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nat Cell Biol. 2011 Sep 02;13(9):1016-23
pubmed: 21892142
Nat Rev Mol Cell Biol. 2018 Feb;19(2):121-135
pubmed: 28974774
Exp Mol Med. 2016 Jul 15;48(7):e245
pubmed: 27416781
Nature. 2018 Aug;560(7719):499-503
pubmed: 30051890
Cancer Cell. 2019 Oct 14;36(4):385-401.e8
pubmed: 31564637
Nat Protoc. 2009;4(8):1184-91
pubmed: 19617889
Cancer Cell. 2016 Jul 11;30(1):147-160
pubmed: 27411589
Eur J Clin Nutr. 2013 Aug;67(8):789-96
pubmed: 23801097
Nat Cell Biol. 2020 Sep;22(9):1064-1075
pubmed: 32839551
Cancer Res. 2016 Jan 15;76(2):227-38
pubmed: 26637667
Mol Cancer Res. 2015 Jul;13(7):1059-72
pubmed: 25956158
Nat Med. 2018 Aug;24(8):1143-1150
pubmed: 30038220
Immunity. 2016 May 17;44(5):955-72
pubmed: 27192563
Annu Rev Nutr. 2006;26:1-22
pubmed: 16848698
Biochem J. 2014 Apr 15;459(2):275-87
pubmed: 24467442
Mol Cell Proteomics. 2010 Jun;9(6):1314-23
pubmed: 20164059
Cancer Immunol Res. 2018 Aug;6(8):921-929
pubmed: 29871885
J Clin Invest. 2001 Oct;108(8):1167-74
pubmed: 11602624
Cancer Prev Res (Phila). 2012 Nov;5(11):1260-72
pubmed: 23034147
Mol Cell. 2012 Apr 27;46(2):212-25
pubmed: 22424773
Nat Rev Cancer. 2016 Mar;16(3):131-44
pubmed: 26911188
Nature. 2016 May 25;534(7605):55-62
pubmed: 27251275
Genome Biol. 2014;15(12):550
pubmed: 25516281
J Biol Chem. 2013 Nov 22;288(47):34041-34051
pubmed: 24106267
Bioinformatics. 2011 Jun 15;27(12):1739-40
pubmed: 21546393
Cancer Cell. 2016 Jul 11;30(1):136-146
pubmed: 27411588
Cell. 2019 Aug 22;178(5):1088-1101.e15
pubmed: 31442402
FEBS Lett. 2008 Jul 23;582(17):2650-4
pubmed: 18593584
Pediatrics. 2007 Mar;119(3):535-43
pubmed: 17332207
Nat Rev Immunol. 2006 Nov;6(11):836-48
pubmed: 17063185
Nature. 2017 Sep 7;549(7670):106-110
pubmed: 28813410
Biochim Biophys Acta. 2015 Oct;1852(10 Pt A):2056-65
pubmed: 26170063
Cell Metab. 2018 Feb 6;27(2):299-313
pubmed: 29153408
Mol Cell. 2018 Jan 18;69(2):279-291.e5
pubmed: 29351847
Nature. 2014 Apr 24;508(7497):541-5
pubmed: 24670654
Cell Metab. 2017 Sep 5;26(3):523-538.e5
pubmed: 28877456
Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62
pubmed: 22436748
Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1724-39
pubmed: 17299079
Nat Commun. 2013;4:3017
pubmed: 24352254
Science. 2016 Aug 26;353(6302):929-32
pubmed: 27563096
BMC Cancer. 2016 May 13;16:310
pubmed: 27178315
Am J Physiol Cell Physiol. 2009 Dec;297(6):C1554-66
pubmed: 19828836
J Biol. 2003;2(4):28
pubmed: 14511394
J Clin Oncol. 2016 Dec 10;34(35):4277-4283
pubmed: 27903152
Trends Pharmacol Sci. 2010 Feb;31(2):89-98
pubmed: 20097433
Nat Commun. 2016 Aug 30;7:12632
pubmed: 27572267
N Engl J Med. 2015 Jul 2;373(1):23-34
pubmed: 26027431
Cell. 2003 Nov 26;115(5):577-90
pubmed: 14651849
N Engl J Med. 2019 Nov 21;381(21):2020-2031
pubmed: 31562796
Nat Commun. 2018 Nov 9;9(1):4728
pubmed: 30413706
Clin Sci (Lond). 2012 Mar;122(6):253-70
pubmed: 22117616
Curr Biol. 2003 Nov 11;13(22):2004-8
pubmed: 14614828
PLoS One. 2019 Jul 31;14(7):e0220360
pubmed: 31365553
Epilepsia. 2011 Mar;52(3):e7-11
pubmed: 21371020
Nat Med. 2007 Jan;13(1):84-8
pubmed: 17159987
Cell Metab. 2020 Oct 6;32(4):676-688.e4
pubmed: 32791100
J Biol Chem. 2007 Nov 9;282(45):32539-48
pubmed: 17728241
Immunity. 2016 Jun 21;44(6):1255-69
pubmed: 27332730
Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3329-35
pubmed: 14985505
Science. 2011 Mar 25;331(6024):1559-64
pubmed: 21436443
Sci Transl Med. 2016 Mar 2;8(328):328rv4
pubmed: 26936508
Nature. 2017 Sep 7;549(7670):101-105
pubmed: 28813417
Mol Cell. 2018 Aug 16;71(4):606-620.e7
pubmed: 30118680
Cancer Discov. 2019 Jan;9(1):34-45
pubmed: 30297358
Nat Rev Immunol. 2018 Mar;18(3):153-167
pubmed: 28990585
Endocrinology. 2011 Aug;152(8):3143-54
pubmed: 21673100
Cell Metab. 2006 Jun;3(6):403-16
pubmed: 16753576
Mol Cell. 2005 Apr 29;18(3):283-93
pubmed: 15866171
Nature. 2018 Jan 4;553(7686):91-95
pubmed: 29160310
Science. 2015 Apr 3;348(6230):56-61
pubmed: 25838373
CA Cancer J Clin. 2010 Jul-Aug;60(4):207-21
pubmed: 20554718