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- Title
Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8<sup>+</sup> T cells.
- Authors
Gemta, Lelisa F.; Siska, Peter J.; Nelson, Marin E.; Gao, Xia; Liu, Xiaojing; Locasale, Jason W.; Yagita, Hideo; Slingluff Jr., Craig L.; Hoehn, Kyle L.; Rathmell, Jeffrey C.; Bullock, Timothy N. J.
- Abstract
Rescuing T cell glycolysis: 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.
- Subjects
T cells; ENOLASE; IMMUNE response; TUMOR-infiltrating immune cells; GLUCOSE metabolism
- Publication
Science Immunology, 2019, Vol 4, Issue 31, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.aap9520