• 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 Prchalova, Jesse Alt, Rana Rais, Barbara S Slusher, and Jonathan D Powell.
• The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
• Science. 2019 Nov 22; 366 (6468): 1013-1021.

AbstractThe 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.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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