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Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses
Ping-Chih Ho1, Jessica Dauz Bihuniak2, Andrew N Macintyre3
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
Abstract:
Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca(2+)-NFAT signaling and effector functions by repressing sarco/ER Ca(2+)-ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions. Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice. This study uncovers new metabolic checkpoints for T cell activity and demonstrates that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy.
Insights
Metabolic reprogramming of tumor-infiltrating T cells by increasing phosphoenolpyruvate (PEP) production enhances anti-tumor immunity. Overexpressing PCK1 in T cells boosts their effector functions, restricting tumor growth and improving survival in mice.
Area of Science:
- Immunology
- Cell Metabolism
- Cancer Biology
Background:
- Activated T cells rely on aerobic glycolysis and anabolic metabolism for optimal function.
- Tumor microenvironments are often glucose-poor, potentially limiting T cell metabolism and anti-tumor activity.
Purpose of the Study:
- To investigate the role of the glycolytic metabolite phosphoenolpyruvate (PEP) in T cell function within the tumor microenvironment.
- To explore metabolic reprogramming of tumor-reactive T cells as an immunotherapy strategy.
Main Methods:
- Investigated the impact of PEP on T cell receptor-mediated signaling and effector functions.
- Overexpressed phosphoenolpyruvate carboxykinase 1 (PCK1) in tumor-specific T cells to increase PEP production.
- Assessed the anti-tumor efficacy of PCK1-overexpressing T cells in melanoma-bearing mice.
Main Results:
- Phosphoenolpyruvate (PEP) was found to sustain T cell receptor-mediated signaling and effector functions by inhibiting sarco/ER Ca(2+)-ATPase (SERCA).
- Overexpression of PCK1 in tumor-specific CD4 and CD8 T cells enhanced their effector functions.
- PCK1-engineered T cells demonstrated significant tumor growth restriction and prolonged survival in preclinical models.
Conclusions:
- Metabolic reprogramming, specifically increasing PEP production via PCK1, can enhance anti-tumor T cell responses.
- This study identifies novel metabolic checkpoints for T cell activity and suggests metabolic manipulation as a promising immunotherapy approach.
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