Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion.
Animals
Azo Compounds
/ pharmacology
CD8-Positive T-Lymphocytes
/ immunology
Caproates
/ pharmacology
Citric Acid Cycle
/ drug effects
Energy Metabolism
Female
Glucose
/ metabolism
Glutamine
/ antagonists & inhibitors
Immunologic Memory
Immunotherapy, Adoptive
Lymphocyte Activation
Lymphocytes, Tumor-Infiltrating
/ immunology
Male
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasms, Experimental
/ drug therapy
Tumor Escape
Tumor Microenvironment
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
22 11 2019
22 11 2019
Historique:
received:
23
09
2018
revised:
21
07
2019
accepted:
25
10
2019
pubmed:
9
11
2019
medline:
22
5
2020
entrez:
9
11
2019
Statut:
ppublish
Résumé
The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a "metabolic checkpoint" for tumor immunotherapy.
Identifiants
pubmed: 31699883
pii: science.aav2588
doi: 10.1126/science.aav2588
pmc: PMC7023461
mid: NIHMS1068876
doi:
Substances chimiques
Azo Compounds
0
Caproates
0
JHU083
0
Glutamine
0RH81L854J
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1013-1021Subventions
Organisme : NCI NIH HHS
ID : R01 CA226765
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA229451
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS103927
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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