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Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.


ABSTRACT: 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.

SUBMITTER: Feng Q 

PROVIDER: S-EPMC9448806 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.

Feng Qiang Q   Liu Zhida Z   Yu Xuexin X   Huang Tongyi T   Chen Jiahui J   Wang Jian J   Wilhelm Jonathan J   Li Suxin S   Song Jiwon J   Li Wei W   Sun Zhichen Z   Sumer Baran D BD   Li Bo B   Fu Yang-Xin YX   Gao Jinming J  

Nature communications 20220906 1


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<sup>+</sup> T cells and augments anti-tumor immunity. Subcutaneous administrat  ...[more]

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2021-07-30 | GSE180991 | GEO