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
  • 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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