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

Sci Immunol. 2019 Jan 25;4(31):eaap9520. doi: 10.1126/sciimmunol.aap9520.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / therapeutic use
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Glucose / metabolism*
  • Glucose Transporter Type 1 / metabolism
  • Glycolysis
  • Hepatitis A Virus Cellular Receptor 2 / antagonists & inhibitors
  • Humans
  • Immunoglobulin G / therapeutic use
  • Immunotherapy, Adoptive
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Melanoma / genetics
  • Melanoma / immunology*
  • Melanoma / metabolism*
  • Melanoma / therapy
  • Mice, Inbred C57BL
  • Phosphopyruvate Hydratase / genetics
  • Phosphopyruvate Hydratase / immunology
  • Phosphopyruvate Hydratase / metabolism*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors

Substances

  • Antineoplastic Agents, Immunological
  • Glucose Transporter Type 1
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Immunoglobulin G
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Phosphopyruvate Hydratase
  • Glucose