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

Qiang Feng, Zhida Liu, Xuexin Yu, Tongyi Huang, Jiahui Chen, Jian Wang, Jonathan Wilhelm, Suxin Li, Jiwon Song, Wei Li, Zhichen Sun, Baran D. Sumer (), Bo Li (), Yang-Xin Fu () and Jinming Gao ()
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Qiang Feng: University of Texas Southwestern Medical Center
Zhida Liu: University of Texas Southwestern Medical Center
Xuexin Yu: University of Texas Southwestern Medical Center
Tongyi Huang: University of Texas Southwestern Medical Center
Jiahui Chen: University of Texas Southwestern Medical Center
Jian Wang: University of Texas Southwestern Medical Center
Jonathan Wilhelm: University of Texas Southwestern Medical Center
Suxin Li: University of Texas Southwestern Medical Center
Jiwon Song: University of Texas Southwestern Medical Center
Wei Li: University of Texas Southwestern Medical Center
Zhichen Sun: University of Texas Southwestern Medical Center
Baran D. Sumer: University of Texas Southwestern Medical Center
Bo Li: University of Texas Southwestern Medical Center
Yang-Xin Fu: University of Texas Southwestern Medical Center
Jinming Gao: University of Texas Southwestern Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32521-8

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