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Available4.9
22 reviewsLactate is a key metabolite produced from glycolytic metabolism of glucose1234567890():,;1234567890():,;molecules, yet it also serves as a primary carbon fuel source for many celltypes. In the tumor-immune microenvironment, effect of lactate on cancer andimmune cells can be highly complex and hard to decipher, which is furtherconfounded by acidic protons, a co-product of glycolysis. Here we show thatlactate is able to increase stemness of CD8+ T cells and augments anti-tumorimmunity. Subcutaneous administration of sodium lactate but not glucose tomice bearing transplanted MC38 tumors results in CD8+ T cell-dependenttumor growth inhibition. Single cell transcriptomics analysis reveals increasedproportion of stem-like TCF-1-expressing CD8+ T cells among intra-tumoralCD3+ cells, a phenotype validated by in vitro lactate treatment of T cells.Mechanistically, lactate inhibits histone deacetylase activity, which results inincreased acetylation at H3K27 of the Tcf7 super enhancer locus, leading toincreased Tcf7 gene expression. CD8+ T cells in vitro pre-treated with lactateefficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice.Our results provide evidence for an intrinsic role of lactate in anti-tumorimmunity independent of the pH-dependent effect of lactic acid, and mightadvance cancer immune therapy.
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4.5
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