Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma.
Animals
Biomarkers, Tumor
CD8-Positive T-Lymphocytes
CRISPR-Cas Systems
Carcinogenesis
/ genetics
Carcinoma, Hepatocellular
/ genetics
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
Gene Knockout Techniques
Humans
Liver
/ metabolism
Liver Neoplasms
/ genetics
Methionine
/ metabolism
Methionine Adenosyltransferase
/ blood
Mice
Mice, Inbred C57BL
Mice, Knockout
S-Adenosylmethionine
/ metabolism
T-Lymphocytes
/ metabolism
Transcriptome
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 03 2021
05 03 2021
Historique:
received:
12
10
2020
accepted:
12
02
2021
entrez:
6
3
2021
pubmed:
7
3
2021
medline:
20
3
2021
Statut:
epublish
Résumé
T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity.
Identifiants
pubmed: 33674593
doi: 10.1038/s41467-021-21804-1
pii: 10.1038/s41467-021-21804-1
pmc: PMC7935900
doi:
Substances chimiques
Biomarkers, Tumor
0
S-Adenosylmethionine
7LP2MPO46S
Methionine
AE28F7PNPL
Mat2a protein, mouse
EC 2.5.1.6
Methionine Adenosyltransferase
EC 2.5.1.6
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1455Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC010313
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC010876
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC010877
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011870
Pays : United States
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