Journal
CELL
Volume 162, Issue 6, Pages 1217-1228Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.08.012
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Funding
- Yale Cancer Center, Yale SPORE in Skin Cancer [5 P50 CA121974]
- Wade F.B. Thompson/Cancer Research Institute-CLIP grant
- Howard Hughes Medical Institute
- Melanoma Research Alliance
- Melanoma Research Foundation
- National Cancer Center
- CCFA award [284879]
- Alliance for Lupus Research
- NIH [R37AI066232, R01AI074699, R01HL108006, R00CA168997, R01AI110613]
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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 Ca2+-NFAT signaling and effector functions by repressing sarco/ER Ca2+-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.
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