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Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

Robert D Leone1, Liang Zhao1, Judson M Englert1

  • 1The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.

Science (New York, N.Y.)
|November 9, 2019
PubMed

Insights

Targeting cancer cell metabolism with glutamine antagonists reshapes the tumor microenvironment. This approach enhances effector T cell function, offering a novel metabolic checkpoint strategy for cancer immunotherapy.

Area of Science:

  • Cancer Biology
  • Immunology
  • Metabolic Pathways

Background:

  • Tumor metabolic characteristics impede immune cell function and cancer immunotherapy.
  • The tumor microenvironment is often immunosuppressive due to metabolic factors.

Purpose of the Study:

  • To investigate the impact of glutamine antagonism on the tumor microenvironment and immune cells.
  • To explore glutamine antagonism as a strategy to overcome metabolic hurdles in cancer immunotherapy.

Main Methods:

  • Utilized a glutamine antagonist in tumor-bearing mice.
  • Analyzed metabolic profiles of cancer cells and effector T cells.
  • Assessed changes in tumor hypoxia, acidosis, and nutrient levels.

Main Results:

  • Glutamine blockade suppressed cancer cell oxidative and glycolytic metabolism.
  • Reduced tumor hypoxia, acidosis, and nutrient depletion were observed.
  • Effector T cells upregulated oxidative metabolism, exhibiting enhanced activation and longevity.

Conclusions:

  • Glutamine antagonism metabolically reshapes the tumor microenvironment, reducing immunosuppression.
  • Divergent metabolic reprogramming between cancer cells and T cells drives antitumor responses.
  • Exploiting this metabolic plasticity via glutamine antagonism represents a promising "metabolic checkpoint" for cancer immunotherapy.

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