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Chang, Chih-Hao; Qiu, Jing; O’Sullivan, David; Buck, Michael D.; Noguchi, Takuro; Curtis, Jonathan D.; Chen, Qiongyu; Gindin, Mariel; Gubin, Matthew M.; van der Windt, Gerritje J.W.; Tonc, Elena; Schreiber, Robert D.; Pearce, Edward J.; Pearce, Erika L.
Cell, 09/2015, Volume: 162, Issue: 6Journal Article
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. Display omitted •Tumor cells and TILs compete for glucose within the tumor niche•Metabolic competition can drive cancer progression•Checkpoint blockade antibodies alter the metabolic balance in a tumor•PD-L1 promotes Akt/mTOR activation and glycolysis in tumor cells Glucose consumption by antigenic tumors can metabolically restrict T cells, directly dampening their effector function and allowing tumor progression. Checkpoint blockade therapy may correct this resource imbalance through a direct effect in the tumor cells.
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