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Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity
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Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity
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Journal Article
Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity
2022
Overview
Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8
+
T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8
+
T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8
+
T cells among intra-tumoral CD3
+
cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the
Tcf7
super enhancer locus, leading to increased
Tcf7
gene expression. CD8
+
T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.
Lactic acid from glycolytic metabolism of cancer cells has been associated with immune suppressive functions. Here authors show that lactate, when depart from the acidic protons, inhibits histone deacetylases in CD8 + T cells, which turns them into potent anti-tumour immune cells.
