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 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.
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA. Electronic address: ping-chih.ho@unil.ch.
authors: Ping-Chih
authors: PC
authors: Ho
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
authors: Jessica Dauz
authors: JD
authors: Bihuniak
authors: Department of Pharmacology and Cancer Biology, Immunology, Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA.
authors: Andrew N
authors: AN
authors: Macintyre
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
authors: Matthew
authors: M
authors: Staron
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Xiaojing
authors: X
authors: Liu
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06519, USA.
authors: Robert
authors: R
authors: Amezquita
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors: Yao-Chen
authors: YC
authors: Tsui
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
authors: Guoliang
authors: G
authors: Cui
authors: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06519, USA.
authors: Goran
authors: G
authors: Micevic
authors: Biophysics Unit, Department of Physiological Sciences II, IDIBELL-University of Barcelona, Fexia Llarga s/n 08907, Spain.
authors: Jose C
authors: JC
authors: Perales
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT 06519, USA.
authors: Steven H
authors: SH
authors: Kleinstein
authors: Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, Department of Medicine, Carver College of Medicine University of Iowa, Iowa City, IA 52242, USA.
authors: E Dale
authors: ED
authors: Abel
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
authors: Karl L
authors: KL
authors: Insogna
authors: Department of Pathology, New York University Langone Medical Center, New York, NY 10016, USA.
authors: Stefan
authors: S
authors: Feske
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Jason W
authors: JW
authors: Locasale
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06519, USA.
authors: Marcus W
authors: MW
authors: Bosenberg
authors: Department of Pharmacology and Cancer Biology, Immunology, Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA.
authors: Jeffrey C
authors: JC
authors: Rathmell
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: susan.kaech@yale.edu.
authors: Susan M
authors: SM
authors: Kaech
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006019:Glycolysis; D006593:Hexokinase / Q000378:metabolism; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D015166:Monitoring, Immunologic; D050778:NFATC Transcription Factors / Q000378:metabolism; D010728:Phosphoenolpyruvate / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000276:immunology; D059016:Tumor Microenvironment
chemical_list: D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D010728:Phosphoenolpyruvate; D006593:Hexokinase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium