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

Chih Hao Chang, Jing Qiu, David O'Sullivan, Michael D. Buck, Takuro Noguchi, Jonathan D. Curtis, Qiongyu Chen, Mariel Gindin, Matthew M. Gubin, Gerritje J.W. Van Der Windt, Elena Tonc, Robert D. Schreiber, Edward J. Pearce, Erika L. Pearce

Research output: Contribution to journalArticle

830 Scopus citations

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.

Original languageEnglish
Pages (from-to)1229-1241
Number of pages13
JournalCell
Volume162
Issue number6
DOIs
StatePublished - Sep 10 2015

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    Chang, C. H., Qiu, J., O'Sullivan, D., Buck, M. D., Noguchi, T., Curtis, J. D., Chen, Q., Gindin, M., Gubin, M. M., Van Der Windt, G. J. W., Tonc, E., Schreiber, R. D., Pearce, E. J., & Pearce, E. L. (2015). Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell, 162(6), 1229-1241. https://doi.org/10.1016/j.cell.2015.08.016