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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Gemta, LF; Siska, PJ; Nelson, ME; Gao, X; Liu, X; Locasale, JW; Yagita, H; Slingluff, CL; Hoehn, KL; Rathmell, JC; Bullock, TNJ

Published Date

  • January 25, 2019

Published In

Volume / Issue

  • 4 / 31

PubMed ID

  • 30683669

Pubmed Central ID

  • 30683669

Electronic International Standard Serial Number (EISSN)

  • 2470-9468

Digital Object Identifier (DOI)

  • 10.1126/sciimmunol.aap9520

Language

  • eng

Conference Location

  • United States