Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses

By Ping-Chih Ho, J. Bihuniak, Andrew N. Macintyre, Matthew M. Staron, Xiaojing Liu, R. Amezquita, Yao-Chen Tsui, Guoliang Cui, G. Micevic, J. C. Perales and 8 more. Cell, 2015

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SUMMARY 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.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/584736bbf207af85d9f944c4ca4e8c269dfacdf4

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Citations in the corpus

The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “In glucoselimiting microenvironments, T cells have insufficient phosphoenolpyruvate (PEP), and T cells with genetically increased PEP production have enhanced effector functions and restricted tumor growth in mice (Ho et al., 2015).”
Bioenergetic insufficiencies due to metabolic alterations regulated by PD-1 are an early driver of CD8+ T cell exhaustion (2016, background): “In agreement with this notion, a recently described glucose deprivation signature (Ho et al., 2015) was enriched in CD8 T cells from clone 13 versus Arm infection at day 8 p.”
LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. (2016, background): “In this re- gard, studies by Chang et al. and Ho et al. have shown that accelerated glucose metabolism of tumor cells leads to glucose deprivation and suppresses anti-tumor T cell effector function (Chang et al., 2015; Ho et al., 2015).”
The Warburg Effect: How Does it Benefit Cancer Cells? (2016, background): “Other studies have identified additional possible signaling mechanisms [23,50].”
L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity (2016, background): “…and T cell survival are particularly crucial in anti-tumor responses because nutrients are often scarce in the tumor microenvironment leading to T cell dysfunction (Chang et al., 2015; Ho et al., 2015), stress, and apoptosis (Alves et al., 2006; Maciver et al., 2008; Siska and Rathmell, 2015).”
T Cell Dysfunction in Cancer (2018, background): “Similar findings in a mouse melanoma model indicated a role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining Ca2+-NFAT signaling and T cell effector function (Ho et al., 2015).”