Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8+ T cells

Abstract

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.