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Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

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Science  07 Nov 2019:
eaav2588
DOI: 10.1126/science.aav2588

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Abstract

The metabolic characteristics of tumors present significant hurdles to immune cell function and cancer immunotherapy. Using a novel 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. In contrast, effector T cells responded to glutamine antagonism by markedly upregulating oxidative metabolism and adopting a long-lived, highly-activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent anti-tumor 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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