2. Academic Validation
  3. Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity

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

  • Nat Commun. 2022 Sep 6;13(1):4981. doi: 10.1038/s41467-022-32521-8.
Qiang Feng # 1,  Zhida Liu # 2,  Xuexin Yu # 3,  Tongyi Huang 1,  Jiahui Chen 1,  Jian Wang 1,  Jonathan Wilhelm 1,  Suxin Li 1,  Jiwon Song 1,  Wei Li 1,  Zhichen Sun 1,  Baran D Sumer 4,  Bo Li 5 6,  Yang-Xin Fu 7 8,  Jinming Gao 9 10 11
Affiliations

Affiliations

  • 1 Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 2 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 3 Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 4 Department of Otolaryngology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
  • 5 Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
  • 6 Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
  • 7 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
  • 8 Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
  • 9 Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
  • 10 Department of Otolaryngology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
  • 11 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
  • # Contributed equally.
PMID: 36068198 DOI: 10.1038/s41467-022-32521-8
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.

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