Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8+ T cells
Menée sur des lymphocytes CD8+ issus de mélanomes d'origine murine ou humaine, cette étude met en évidence une corrélation entre le dysfonctionnement de l'énolase 1, une enzyme impliquée dans la glycolyse, et le dysfonctionnement des lymphocytes T CD8+ ayant infiltré la tumeur
One reason T cells in the tumor microenvioronment (TME) become dysfunctional is that they compete with cancer cells for nutrients, particularly glucose. By studying the glucose metabolism of CD8+ T cells in the TME of mouse B16 and human melanomas, Gemta et al. report the activity of enzyme enolase 1 to be impaired. Enolase 1 catalyzes the synthesis of phosphenolpyruvate, which is dephosphorylated to generate pyruvate, the end product of glycolysis. In vitro, provision of pyruvate considerably improved the effector functions of CD8+ T cells isolated from murine melanomas. Pinning down enolase 1 as the rate-limiting step in glucose metabolism of tumor-infiltrating T cells begs the question whether targeting enolase 1 activity in these cells can be used to improve responsiveness to cancer immunotherapy.In the context of solid tumors, there is a positive correlation between the accumulation of cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) and favorable clinical outcomes. However, CD8+ TILs often exhibit a state of functional exhaustion, limiting their activity, and the underlying molecular basis of this dysfunction is not fully understood. Here, we show that TILs found in human and murine CD8+ melanomas are metabolically compromised with deficits in both glycolytic and oxidative metabolism. Although several studies have shown that tumors can outcompete T cells for glucose, thus limiting T cell metabolic activity, we report that a down-regulation in the activity of ENOLASE 1, a critical enzyme in the glycolytic pathway, represses glycolytic activity in CD8+ TILs. Provision of pyruvate, a downstream product of ENOLASE 1, bypasses this inactivity and promotes both glycolysis and oxidative phosphorylation, resulting in improved effector function of CD8+ TILs. We found high expression of both enolase 1 mRNA and protein in CD8+ TILs, indicating that the enzymatic activity of ENOLASE 1 is regulated posttranslationally. These studies provide a critical insight into the biochemical basis of CD8+ TIL dysfunction.
Science Immunology , article en libre accès, 2018