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Published on: May 6, 2019
Differential Effects of Glutamine Inhibition Strategies on Antitumor CD8 T Cells
Matthew Z Madden1, Xiang Ye1, Channing Chi1
1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN.
Abstract:
Activated T cells undergo metabolic reprogramming to meet anabolic, differentiation, and functional demands. Glutamine supports many processes in activated T cells, and inhibition of glutamine metabolism alters T cell function in autoimmune disease and cancer. Multiple glutamine-targeting molecules are under investigation, yet the precise mechanisms of glutamine-dependent CD8 T cell differentiation remain unclear. We show that distinct strategies of glutamine inhibition by glutaminase-specific inhibition with small molecule CB-839, pan-glutamine inhibition with 6-diazo-5-oxo-l-norleucine (DON), or by glutamine-depleted conditions (No Q) produce distinct metabolic differentiation trajectories in murine CD8 T cells. T cell activation with CB-839 treatment had a milder effect than did DON or No Q treatment. A key difference was that CB-839-treated cells compensated with increased glycolytic metabolism, whereas DON and No Q-treated cells increased oxidative metabolism. However, all glutamine treatment strategies elevated CD8 T cell dependence on glucose metabolism, and No Q treatment caused adaptation toward reduced glutamine dependence. DON treatment reduced histone modifications and numbers of persisting cells in adoptive transfer studies, but those T cells that remained could expand normally upon secondary Ag encounter. In contrast, No Q-treated cells persisted well yet demonstrated decreased secondary expansion. Consistent with reduced persistence, CD8 T cells activated in the presence of DON had reduced ability to control tumor growth and reduced tumor infiltration in adoptive cell therapy. Overall, each approach to inhibit glutamine metabolism confers distinct effects on CD8 T cells and highlights that targeting the same pathway in different ways can elicit opposing metabolic and functional outcomes.
Insights
Targeting glutamine metabolism in CD8 T cells impacts their differentiation and function differently. Different inhibition strategies lead to distinct metabolic shifts and opposing outcomes in immune response and cancer therapy.
Area of Science:
- Immunology
- Cellular Metabolism
- Cancer Biology
Background:
- Activated T cells require metabolic reprogramming for differentiation and function.
- Glutamine metabolism is crucial for T cell processes, influencing autoimmune disease and cancer.
- Precise mechanisms of glutamine-dependent CD8 T cell differentiation are not fully understood.
Purpose of the Study:
- To investigate the distinct effects of various glutamine metabolism inhibition strategies on murine CD8 T cell differentiation.
- To elucidate the metabolic and functional consequences of targeting glutamine metabolism in CD8 T cells.
Main Methods:
- Utilized glutaminase-specific inhibitor (CB-839), pan-glutamine inhibitor (6-diazo-5-oxo-l-norleucine, DON), and glutamine-depleted conditions (No Q) to inhibit glutamine metabolism.
- Analyzed metabolic profiles (glycolysis, oxidative metabolism) and functional outcomes (differentiation, persistence, secondary expansion, tumor control) of CD8 T cells.
- Employed adoptive transfer studies and tumor models to assess in vivo efficacy.
Main Results:
- CB-839 treatment showed milder effects, with cells compensating via increased glycolysis.
- DON and No Q treatments led to increased oxidative metabolism, with No Q inducing adaptation to reduced glutamine dependence.
- All strategies increased CD8 T cell dependence on glucose metabolism.
- DON treatment reduced histone modifications and cell persistence, while No Q-treated cells persisted but had decreased secondary expansion.
- DON-treated CD8 T cells showed reduced tumor control and infiltration in adoptive cell therapy.
Conclusions:
- Distinct strategies for inhibiting glutamine metabolism elicit unique metabolic differentiation trajectories in CD8 T cells.
- Targeting glutamine metabolism can lead to opposing metabolic and functional outcomes, impacting T cell-mediated immunity and cancer therapy.
- Understanding these differential effects is crucial for developing effective immunotherapies.
