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

Ping Chih Ho; Jessica Dauz Bihuniak; Andrew N. MacIntyre; Matthew Staron; Xiaojing Liu; Robert Amezquita; Yao Chen Tsui; Guoliang Cui; Goran Micevic; Jose C. Perales; Steven H. Kleinstein; E. Dale Abel; Karl L. Insogna; Stefan Feske; Jason W. Locasale; Marcus W. Bosenberg; Jeffrey C. Rathmell; Susan M. Kaech

doi:10.1016/j.cell.2015.08.012

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

Ping Chih Ho, Jessica Dauz Bihuniak, Andrew N. MacIntyre, Matthew Staron, Xiaojing Liu, Robert Amezquita, Yao Chen Tsui, Guoliang Cui, Goran Micevic, Jose C. Perales, Steven H. Kleinstein, E. Dale Abel, Karl L. Insogna, Stefan Feske, Jason W. Locasale, Marcus W. Bosenberg, Jeffrey C. Rathmell, Susan M. Kaech

Nutrition and Food Studies

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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 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.

Original language	English (US)
Pages (from-to)	1217-1228
Number of pages	12
Journal	Cell
Volume	162
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2015.08.012
State	Published - Sep 10 2015

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2015.08.012

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Ho, P. C., Bihuniak, J. D., MacIntyre, A. N., Staron, M., Liu, X., Amezquita, R., Tsui, Y. C., Cui, G., Micevic, G., Perales, J. C., Kleinstein, S. H., Abel, E. D., Insogna, K. L., Feske, S., Locasale, J. W., Bosenberg, M. W., Rathmell, J. C., & Kaech, S. M. (2015). Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell, 162(6), 1217-1228. https://doi.org/10.1016/j.cell.2015.08.012

Ho, PC, Bihuniak, JD, MacIntyre, AN, Staron, M, Liu, X, Amezquita, R, Tsui, YC, Cui, G, Micevic, G, Perales, JC, Kleinstein, SH, Abel, ED, Insogna, KL, Feske, S, Locasale, JW, Bosenberg, MW, Rathmell, JC & Kaech, SM 2015, 'Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses', Cell, vol. 162, no. 6, pp. 1217-1228. https://doi.org/10.1016/j.cell.2015.08.012

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title = "Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses",

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 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.",

author = "Ho, {Ping Chih} and Bihuniak, {Jessica Dauz} and MacIntyre, {Andrew N.} and Matthew Staron and Xiaojing Liu and Robert Amezquita and Tsui, {Yao Chen} and Guoliang Cui and Goran Micevic and Perales, {Jose C.} and Kleinstein, {Steven H.} and Abel, {E. Dale} and Insogna, {Karl L.} and Stefan Feske and Locasale, {Jason W.} and Bosenberg, {Marcus W.} and Rathmell, {Jeffrey C.} and Kaech, {Susan M.}",

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year = "2015",

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doi = "10.1016/j.cell.2015.08.012",

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AU - Ho, Ping Chih

AU - Bihuniak, Jessica Dauz

AU - MacIntyre, Andrew N.

AU - Staron, Matthew

AU - Liu, Xiaojing

AU - Amezquita, Robert

AU - Tsui, Yao Chen

AU - Cui, Guoliang

AU - Micevic, Goran

AU - Perales, Jose C.

AU - Kleinstein, Steven H.

AU - Abel, E. Dale

AU - Insogna, Karl L.

AU - Feske, Stefan

AU - Locasale, Jason W.

AU - Bosenberg, Marcus W.

AU - Rathmell, Jeffrey C.

AU - Kaech, Susan M.

PY - 2015/9/10

Y1 - 2015/9/10

N2 - 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.

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

Abstract

ASJC Scopus subject areas

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