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Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion
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Journal Article
Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion
2019
Overview
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.
Publisher
American Association for the Advancement of Science,The American Association for the Advancement of Science
Subject
/ Animals
/ Azo Compounds - pharmacology
/ Cancer
/ CD8-Positive T-Lymphocytes - immunology
/ Citric Acid Cycle - drug effects
/ Female
/ Glutamine - antagonists & inhibitors
/ Hypoxia
/ Lymphocytes, Tumor-Infiltrating - immunology
/ Male
/ Neoplasms, Experimental - drug therapy
/ Neoplasms, Experimental - immunology
/ Neoplasms, Experimental - metabolism
/ Neoplasms, Experimental - therapy
/ Tumors
