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 - Funding Information:
We thank A. Shaw, C. Hsieh, H. Christofk, J. Cyster, Y. Feng, B. Edelson J. Lin, J. Hu, H. Yu, M. Colonna, A. Fuchs, G. Randolph, and L. Huang. This work was supported by grants from the NIH (CA181125, AI091965 to E.L.P.; CA43059, CA141541 to R.D.S.; CA164062, AI032573 to E.J.P.), The Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease (E.L.P.), CRI, WWWW Foundation, and BMS (R.D.S), Irvington Fellowship (M.M.G.), Netherlands Organisation for Scientific Research (G.J.W.v.d.W.), and NSF Graduate Research Fellowship DGE-1143954 (M.D.B.). Robert Schreiber is a cofounder of Igenica Biotherapeutics, and is a senior advisor to Jounce Therapeutics.
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.
UR - http://www.scopus.com/inward/record.url?scp=84941344937&partnerID=8YFLogxK
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 -