Journal
SCIENCE
Volume 366, Issue 6468, Pages 1013-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aav2588
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Funding
- National Institutes of Health [R01CA226765, R01CA229451]
- Bloomberg-Kimmel Institute for Cancer Immunotherapy
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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.
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