title: Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression.
abstract: Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic "regressor" tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-γ production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer.
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Chih-Hao
authors: CH
authors: Chang
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Jing
authors: J
authors: Qiu
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: David
authors: D
authors: O'Sullivan
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Michael D
authors: MD
authors: Buck
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Takuro
authors: T
authors: Noguchi
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Jonathan D
authors: JD
authors: Curtis
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Qiongyu
authors: Q
authors: Chen
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Mariel
authors: M
authors: Gindin
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Matthew M
authors: MM
authors: Gubin
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Gerritje J W
authors: GJ
authors: van der Windt
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Elena
authors: E
authors: Tonc
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Robert D
authors: RD
authors: Schreiber
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Edward J
authors: EJ
authors: Pearce
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA. Electronic address: pearce@ie-freiburg.mpg.de.
authors: Erika L
authors: EL
authors: Pearce
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D006019:Glycolysis; D007371:Interferon-gamma / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology; D059016:Tumor Microenvironment
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma