TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy

Lingyun Li, Xia Liu, Katherine L. Sanders, James L. Edwards, Jian Ye, Fusheng Si, Aiqin Gao, Lan Huang, Eddy C. Hsueh, David A. Ford, Daniel F. Hoft, Guangyong Peng

Research output: Contribution to journalArticlepeer-review

118 Scopus citations


Regulatory T (Treg) cells induce an immunosuppressive microenvironment that is a major obstacle for successful tumor immunotherapy. Dissecting the regulatory mechanisms between energy metabolism and functionality in Treg cells will provide insight toward developing novel immunotherapies against cancer. Here we report that human naturally occurring and tumor-associated Treg cells exhibit distinct metabolic profiles with selectivity for glucose metabolism compared with effector T cells. Treg-mediated accelerated glucose consumption induces cellular senescence and suppression of responder T cells through cross-talk. TLR8 signaling selectively inhibits glucose uptake and glycolysis in human Treg cells, resulting in reversal of Treg suppression. Importantly, TLR8 signaling-mediated reprogramming of glucose metabolism and function in human Treg cells can enhance anti-tumor immunity in vivo in a melanoma adoptive transfer T cell therapy model. Our studies identify mechanistic links between innate signaling and metabolic regulation of human Treg suppression, which may be used as a strategy to advance tumor immunotherapy.

Original languageEnglish
Pages (from-to)103-123.e5
JournalCell metabolism
Issue number1
StatePublished - Jan 8 2019


  • adoptive transfer T cell therapy
  • glycolysis
  • metabolism
  • metabolite
  • T cell senescence
  • T cell subsets
  • Toll-like receptor
  • Treg cells
  • tumor immunotherapy
  • tumor suppressive microenvironment


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