Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression
A l'aide d'un modèle murin de sarcome, cette étude met en évidence des mécanismes par lesquels la compétition métabolique entre les cellules tumorales et les lymphocytes T favorise la progression tumorale
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.