Tumor Glucose Consumption Inhibits T-cell Function

T-cell dysfunction is thought to contribute to immune system evasion by tumor cells and can be caused by multiple environmental factors. For example, in vitro experiments suggest that proper T-cell function is dependent on glucose, which can be in low supply within the tumor microenvironment. Using a mouse sarcoma model, Chang, Qiu, and colleagues showed T cells produced significantly less IFNγ when cultured with tumor cells than when cultured alone, but that the addition of glucose could restore IFNγ production, suggesting that competition with tumor cells for glucose suppresses T-cell activation. Compared with an antigenic sarcoma clone that regresses in vivo, progressor sarcomas displayed increased glycolytic activity, and tumor-infiltrating lymphocytes (TIL) isolated from progressor tumors were hyporesponsive and showed reduced glycolysis and increased markers of nutrient deprivation, demonstrating that tumor cells suppress T-cell function by limiting glucose availability in the extracellular milieu. Consistent with this possibility, increasing regressor tumor cell glycolysis by increasing glucose exposure or overexpressing MYC was sufficient to reverse regression and promote tumor growth. Immune checkpoint blockade therapy enhanced glycolytic activity and cytokine production in TILs by directly inhibiting AKT/mTOR-driven glycolysis in tumor cells, providing evidence for a function of immune checkpoint inhibitors beyond direct regulation of T-cell signaling. Ho and colleagues similarly observed that glucose limitation in the tumor microenvironment and increased tumor glycolysis dampen TIL activation, and showed that low T-cell levels of phosphoenolpyruvate (PEP), a glycolytic metabolite that inhibits the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), reduces Ca²⁺ and NFAT1 signaling and thus suppresses antitumor responses. Metabolic rewiring of T cells by overexpressing phosphoenolpyruvate carboxykinase 1 increased PEP production and T-cell effector function and suppressed tumor growth. Together, these studies illustrate how tumor cell–induced metabolic reprogramming of T cells suppresses their activation and provide further insight into the mechanism of action of immune checkpoint inhibitors and potential strategies to boost antitumor immunity.

Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 2015;162:1229–41.

Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 2015;162:1217–28.

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