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

Gemta LF, Siska PJ, Nelson ME, Gao X, Liu X, Locasale JW, Yagita H, Slingluff CL, Hoehn KL, Rathmell JC, Bullock TNJ
Sci Immunol. 2019 4 (31)

PMID: 30683669 · PMCID: PMC6824424 · DOI:10.1126/sciimmunol.aap9520

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.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

MeSH Terms (16)

Animals Antineoplastic Agents, Immunological CD8-Positive T-Lymphocytes Cell Line, Tumor Glucose Glucose Transporter Type 1 Glycolysis Hepatitis A Virus Cellular Receptor 2 Humans Immunoglobulin G Immunotherapy, Adoptive Lymphocytes, Tumor-Infiltrating Melanoma Mice, Inbred C57BL Phosphopyruvate Hydratase Programmed Cell Death 1 Receptor

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