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

• DOI: 10.1038/s41467-022-32521-8
• Publication Date: 2022-09-06T10:03:01Z
• Authors: 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; Jinming Gao
• Keywords: 0301 basic medicine; Science; Q; CD8-Positive T-Lymphocytes; Article; 3. Good health; Mice; 03 medical and health sciences; Cell Line, Tumor; Neoplasms; Tumor Microenvironment; Animals; Lactic Acid; Glycolysis

AbstractLactate 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.