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Glycolysis and EZH2 boost T cell weaponry against tumors

Nature Immunology volume 17, pages 41–42 (2016)Cite this article

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Low availability of glucose in tumors negatively affects the activity of tumor-infiltrating T cells. Loss of T cell function under these conditions is mediated by the microRNAs miR-101 and miR-26a, which target expression of the methytransferase EZH2 and thereby diminish the expression of anti-tumor cytokines.

T cells are essential for the elimination of pathogen-infected cells and tumor cells. The differentiation of naive and memory T cells into effector populations requires a switch from catabolic metabolism to anabolic metabolism, which is reflected by enhanced aerobic glycolysis and mitochondrial respiration. Both of these metabolic pathways provide the energy and building blocks for biomolecular synthesis that are required for the clonal expansion of antigen-specific T cells. Reprogramming of metabolic pathways is not only fundamental for the clonal expansion of T cells but also critical for the elaboration of effector molecules. CD4+ T cells that do not engage glycolysis during activation produce less interferon-γ (IFN-γ), due to deficits in the translation of IFN-γ mRNA1. In memory CD8+ T cells, direct pharmacological blockade of glycolysis or inhibition of the serine-threonine kinase Akt, a critical regulator of glucose metabolism, also diminishes IFN-γ production2. Decreased glycolysis in memory CD8+ T cells results in lower expression of the gene encoding IFN-γ (IFNG) via alterations in the acetylation of histone H3 at Lys9 in the IFNG promoter2. Thus, glycolysis affects IFN-γ production by controlling both the transcription of IFNG and translation of IFN-γ. In this issue of Nature Immunology, Zou and colleagues provide evidence that glucose availability affects T cell polyfunctionality by modifying expression of the microRNAs (miRNAs) miR-101 and miR-26a and the methytransferase EZH2 in T cells3.

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Figure 1: The effect of glucose restriction on the function of tumor infiltrating lymphocytes.

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  1. Glenn R. Bantug and Christoph Hess are in the Department of Biomedicine, University of Basel, Basel, Switzerland.,

    Glenn R Bantug & Christoph Hess

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  1. Glenn R Bantug
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  2. Christoph Hess
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Correspondence to Christoph Hess.

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Bantug, G., Hess, C. Glycolysis and EZH2 boost T cell weaponry against tumors. Nat Immunol 17, 41–42 (2016). https://doi.org/10.1038/ni.3346

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