Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Cell, 2015-09, Vol.162 (6), p.1229-1241

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.