Cell
Volume 162, Issue 6, 10 September 2015, Pages 1229-1241
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Article
Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression

https://doi.org/10.1016/j.cell.2015.08.016Get rights and content
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Highlights

  • 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

Summary

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.

Cited by (0)

2

Co-first author

3

Present Address: Academic Medical Center, 1105 AZ Amsterdam, Netherlands

4

Present Address: Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany