Gemta, Lelisa F. and Siska, Peter J. and Nelson, Marin E. and Gao, Xia and Liu, Xiaojing and Locasale, Jason W. and Yagita, Hideo and Slingluff, Craig L. and Hoehn, Kyle L. and Rathmell, Jeffrey C. and Bullock, Timothy N. J. (2019) Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8(+) T cells. SCIENCE IMMUNOLOGY, 4 (31): eaap9520. ISSN 2470-9468,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | METABOLIC REQUIREMENTS; GLUCOSE-UPTAKE; ACTIVATION; PD-1; MICROENVIRONMENT; DIFFERENTIATION; EXHAUSTION; EXPRESSION; BINDING; DRIVER; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Apr 2020 06:11 |
| Last Modified: | 22 Apr 2020 06:11 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27870 |
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