TY - JOUR
T1 - Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression
AU - Chang, Chih Hao
AU - Qiu, Jing
AU - O'Sullivan, David
AU - Buck, Michael D.
AU - Noguchi, Takuro
AU - Curtis, Jonathan D.
AU - Chen, Qiongyu
AU - Gindin, Mariel
AU - Gubin, Matthew M.
AU - Van Der Windt, Gerritje J.W.
AU - Tonc, Elena
AU - Schreiber, Robert D.
AU - Pearce, Edward J.
AU - Pearce, Erika L.
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/9/10
Y1 - 2015/9/10
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2015.08.016
DO - 10.1016/j.cell.2015.08.016
M3 - Article
C2 - 26321679
AN - SCOPUS:84941344937
SN - 0092-8674
VL - 162
SP - 1229
EP - 1241
JO - Cell
JF - Cell
IS - 6
ER -