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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.

SUBMITTER: Gemta LF 

PROVIDER: S-EPMC6824424 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8<sup>+</sup> T cells.

Gemta Lelisa F LF   Siska Peter J PJ   Nelson Marin E ME   Gao Xia X   Liu Xiaojing X   Locasale Jason W JW   Yagita Hideo H   Slingluff Craig L CL   Hoehn Kyle L KL   Rathmell Jeffrey C JC   Bullock Timothy N J TNJ  

Science immunology 20190101 31


In the context of solid tumors, there is a positive correlation between the accumulation of cytotoxic CD8<sup>+</sup> tumor-infiltrating lymphocytes (TILs) and favorable clinical outcomes. However, CD8<sup>+</sup> 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<sup>+</sup> melanomas are metabolically compromised with deficits in both  ...[more]

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