Metabolic competition in the tumor microenvironment is a driver of cancer progression

By Chih-Hao Chang, J. Qiu, David O’Sullivan, Michael D. Buck, T. Noguchi, Jonathan D. Curtis, Qiongyu Chen, Mariel Gindin, M. Gubin, G. V. D. van der Windt and 4 more. Cell, 2015

2,891 citations recorded by the source corpus.

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 tumors, 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.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/477a838bedb4d643004ef2e779c7b7661c58d6fa

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Citations in the corpus

Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity (2020, background): “Given the limited blood supply of solid tumors, high nutrient consumption by tumor cells may pose a barrier to the metabolic requirements of intratumoral T cells (Chang et al., 2015; Ho et al., 2015).”
Understanding the intersections between metabolism and cancer biology (2017, neutral): “Cancer cells compete with T cells for glucose in tumors, and restricting T cell glucose metabolism causes lymphocyte exhaustion (Chang et al., 2015; Ho et al., 2015).”
Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy. (2020, background): “Carbonic anhydrase IX (CAIX) maintains extracellular acidity under hypoxic conditions, and CAIX-targeting antibodies have been found to improve TME pH and enhance immune-mediated killing of CAIX+ tumor cells (D. K. Chang et al., 2015).”
Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology (2020, background): “Glucose restrictions within the tumour microenvironment as a result of increased glucose uptake of hypoxic tumour cells can also favour the activation of an M2-like phenotype in tumour infiltrating macrophages, thereby promoting an anti-inflammatory response and promoting tumour growth (Chang et al.”
Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “This importance of glycolysis for optimal Te cell function was recently demonstrated in vivo using a sarcoma tumor model, where immune evasion of tumors directly correlates with their ability to compete for glucose with tumor-infiltrating lymphocytes (TILs) (78).”