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 TILss found in human and murine CD8+ melanomas are metabolically compromised with deficits in both glycolytic and oxidative metabolism. While several studies have shown that tumors can outcompete T cells for glucose, thus limiting T cell metabolic activity, we report that a down-regulation of 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 post-translationally. These studies provide a critical insight into the biochemical basis of CD8+ TILs dysfunction.

In Silico Modeling of Metabolic State in Single Th17 Cells Reveals Novel Regulators of Inflammation and Autoimmunity

“…To this end, we studied the impact of PDK4-deficiency on the development of EAE, an autoimmune disease induced by pathogenic Th17 cells. Consistent with previous studies that glycolysis promotes inflammation [57], [69]- [71], mice with global knockout of PDK4 developed less severe disease as determined by the clinical disease scores ( Figure 3H) with decrease in Th17 cells and increase in the infiltration of Foxp3 + Tregs in the CNS of the mice undergoing EAE (Figure 3I). We therefore conclude that PDK4-deficient Th17p cells resemble Th17n in their central carbon metabolic state, but not in other metabolic pathways.…”

“…The most notable of these reactions was the one catalyzed by the enzyme phosphoglycerate mutase (PGAM), which was negatively associated with pathogenicity in the intra-population analysis of Th17n cells ( Figure 4A), but positively associated with Th17p cells in the inter-population analysis ( Figure 2B,C). This prediction was unexpected because increased glycolysis is generally known to support pro-inflammatory phenotypes in T cells (see also Discussion) [55]- [57], [69], [72]- [78].…”

Prognostic Value of Tumor-Infiltrating Lymphocytes Differs Depending on Lymphocyte Subsets in Esophageal Squamous Cell Carcinoma: An Updated Meta-Analysis

“…Similarly, Chen et al showed that the expression of B7-H4 on esophageal cancer cells is inversely correlated with the densities of CD8+ TILs, suggesting that B7-H4 inhibits TILs recruitment (23). In addition, the impaired function of CD8+ TILs may also be mediated by immunosuppressing factors released by tumor cells, deficient presentation of tumor antigen by dendritic cells, and reduced production of co-stimulating cytokines by helper CD4+ T-cells (42,43).…”

Anxiolytic Drug FGIN-1-27 Ameliorates Autoimmunity by Metabolic Reprogramming of Pathogenic Th17 Cells

“…Th17 cells are heavily dependent on glycolysis for their development and maintenance 13,14,30 . Likewise, anergic T cells and dysfunctional tumor infiltrating lymphocytes are reported to have defects in glycolytic pathway [31][32][33] and deficiency in glucose transporter glut1 has been linked with decreased effector function and protection from inflammatory diseases 34 . We detected reduction in expression of glucose transporter Glut3 (GEO accession GSE128308) in addition to all the transcripts encoding enzymes glycolytic enzymes leading us to conclude that FGIN-1-27 treatment alters the glycolytic pathway in Th17 cells, thus demonstrating that a small molecule can be used to alter the glycolytic machinery in a cell to achieve a desirable immune response.…”