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Immunometabolism

CD8+ T cells pass the acid test

Nature Metabolism volume 5, pages 201–202 (2023)Cite this article

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Lactate build up in the tumour microenvironments is thought to dampen anti-tumour immunity, but in vitro pre-conditioning T cells with lactate enhances anti-tumour activity in vivo in pre-clinical mouse models.

Strikingly, long-term culture of CD8+ T cells induced expression of Tcf1 (encoded by Tcf7) and the memory markers Ccr7 and CD62L; this is closely correlated with a previously published stem-cell like phenotype3. A similar study showed that direct lactate injection in vivo induced T cell stemness in CD8+ T cells, improving the efficacy of cancer immunotherapies in preclinical models4. Despite both studies highlighting a role for lactate-induced epigenetic remodelling, the mechanisms proposed differ considerably. Where one study proposed a role for lactate (independent of pH) in suppression of histone deacetylases altering the acetylome4, Cheng et al. proposed another layer of regulation by which ↑[H+]-treated T cells show broad scope methylome differences compared to control cells as a result of metabolic alterations. Epigenetic remodelling is crucial for CD8+ T cell function and can be impacted by alterations in metabolic pathway activities, leading to altered availability of key metabolic intermediates including S-adenosyl-methionine (SAM), a key methyl donor that allows regulation of chromatin accessibility via methylation5. In ↑[H+]-treated T cells, H3K27me3, a histone mark associated with reduced transcription, was increased at the gene loci of key effector molecules (Prf1, Gzmb and Infg), but was decreased in the gene loci of memory associated markers, including Tcf7 and Ccr7. Taken together, these results suggest that the acidic environment induces epigenetic stemness in T cells.

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Fig. 1: Pre-conditioning CD8+ T cells in acidic media (↑[H+]; 10 mM lactate or pH 6.6) increased in vivo anti-tumour function by inducing a stem cell-like gene expression program as a result of metabolic rewiring.

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Acknowledgements

A.S.A. received a postdoctoral fellowship award from the Michael Smith Foundation of Health Research British Columbia, J.H.O. received a 4-Year fellowship from the University of British Columbia and R.I.K.G. received a Scholar award from the Michael Smith Foundation of Health Research British Columbia.

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  1. These authors contributed equally: Ju Hee Oh, Anne-Sophie Archambault.

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  1. BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada

    Ju Hee Oh, Anne-Sophie Archambault & Ramon I. Klein Geltink

  2. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Ju Hee Oh, Anne-Sophie Archambault & Ramon I. Klein Geltink

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  1. Ju Hee Oh
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Correspondence to Ramon I. Klein Geltink.

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Oh, J.H., Archambault, AS. & Klein Geltink, R.I. CD8+ T cells pass the acid test. Nat Metab 5, 201–202 (2023). https://doi.org/10.1038/s42255-023-00738-6

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