Glutamine Blockade Induces Divergent Metabolic Programs to Overcome Tumor Immune Evasion

Science. 2019 Nov 22;366(6468):1013-1021. doi: 10.1126/science.aav2588. Epub 2019 Nov 7.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azo Compounds / pharmacology*
  • CD8-Positive T-Lymphocytes / immunology
  • Caproates / pharmacology*
  • Citric Acid Cycle / drug effects
  • Energy Metabolism
  • Female
  • Glucose / metabolism
  • Glutamine / antagonists & inhibitors
  • Glutamine / metabolism*
  • Immunologic Memory
  • Immunotherapy, Adoptive*
  • Lymphocyte Activation
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / therapy*
  • Tumor Escape*
  • Tumor Microenvironment

Substances

  • Azo Compounds
  • Caproates
  • JHU083
  • Glutamine
  • Glucose