S-2HG acts as an immunometabolite to regulate CD8+ T cell fate, promoting persistence and survival.

  • Major finding: S-2HG acts as an immunometabolite to regulate CD8+ T cell fate, promoting persistence and survival.

  • Mechanism: HIF1α promotes production of S-2HG in CD8+ T cells in response to hypoxia and TCR triggering.

  • Impact: S-2HG treatment may block differentiation of adoptively transferred T cells to improve cancer therapy.

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CD8+ T-lymphocytes respond to T-cell receptor (TCR) triggering by transitioning to a proliferative effector state. These effector T cells can infiltrate hypoxic regions of tumors and experience a metabolic shift toward ATP production via glycolysis. The response to hypoxia is mediated by hypoxia inducible transcription factor α (HIF1α), which is negatively regulated by von Hippel-Lindau protein (VHL). To better understand the metabolic effects of HIF1α activation, Tyrakis and colleagues performed metabolic profiling of CD8+ T lymphocytes with low HIF signaling (Vhl-proficient), high HIF signaling (Vhl-conditional knockout), and conditional Hif1α;Vhl double knockout. Levels of 2-hydroxyglutarate (2HG) were increased in Vhl-deficient CD8+ T-lymphocytes, but not when Hif1α was also deleted, indicating that the VHL–HIF axis regulates levels of 2HG. It has been previously shown that while both the R-2HG and S-2HG enantiomers are expressed in healthy individuals, R-2HG accumulates in cancers with gain-of-function IDH1/2 mutations, whereas S-2HG accumulates in hypoxia and mitochondrial dysfunction. Accordingly, 2HG levels were increased in activated CD8+ T-lymphocytes, with greater increases in hypoxic conditions, and S-2HG comprised the majority of the cellular 2HG pool. Further, Hif1α loss prevented the accumulation of S-2HG. S-2HG treatment altered the transcriptional program of CD8+ T-lymphocytes, suppressing T-cell differentiation and promoting long-term persistence. In addition, S-2HG altered the methylation profile of CD8+ T cells, decreasing 5-hydroxymethylcytosine and increasing 5-methylcytosine, and also altered histone methylation. In vivo, adoptive transfer of S-2HG-treated CD8+ T-lymphocytes into mice enhanced their persistence and antitumor activity. Collectively, these findings define a role for S-2HG as an immunometabolite that controls T-cell fate, and suggest that S-2HG might enhance the efficacy of adoptively transferred T cells.

Tyrakis PA, Palazon A, Macias D, Lee KL, Phan AT, Veliça P, et al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 2016 Oct 26 [Epub ahead of print].

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.