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Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

2019; American Association for the Advancement of Science; Volume: 366; Issue: 6468 Linguagem: Inglês

10.1126/science.aav2588

1095-9203

Robert D. Leone, Liang Zhao, Judson M. Englert, Im-Meng Sun, Min Hee Oh, Im‐Hong Sun, Matthew L. Arwood, Ian A. Bettencourt, Chirag H. Patel, Jiayu Wen, Ada Tam, Richard L. Blosser, Eva Prchalová, Jesse Alt, Rana Rais, Barbara S. Slusher, Jonathan D. Powell,

Cancer Research and Treatments

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.