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      Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression.

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          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.

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          Author and article information

          Journal
          Cell
          Cell
          1097-4172
          0092-8674
          Sep 10 2015
          : 162
          : 6
          Affiliations
          [1 ] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
          [2 ] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA. Electronic address: pearce@ie-freiburg.mpg.de.
          Article
          S0092-8674(15)01029-6 NIHMS715339
          10.1016/j.cell.2015.08.016
          26321679
          bd1187dd-9850-4da0-846d-6faef279938c
          Copyright © 2015 Elsevier Inc. All rights reserved.
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