2. Academic Validation
  3. TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy

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

  • Cell Metab. 2019 Jan 8;29(1):103-123.e5. doi: 10.1016/j.cmet.2018.09.020.
Lingyun Li 1,  Xia Liu 2,  Katherine L Sanders 3,  James L Edwards 3,  Jian Ye 4,  Fusheng Si 4,  Aiqin Gao 4,  Lan Huang 2,  Eddy C Hsueh 5,  David A Ford 6,  Daniel F Hoft 7,  Guangyong Peng 8
Affiliations

Affiliations

  • 1 Division of Infectious Diseases, Allergy & Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA; Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, P. R. China.
  • 2 Division of Infectious Diseases, Allergy & Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA; Department of Immunology, Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, P. R. China.
  • 3 Department of Chemistry, Saint Louis University, Saint Louis, MO 63103, USA.
  • 4 Division of Infectious Diseases, Allergy & Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA.
  • 5 Division of General Surgery, Department of Surgery, Saint Louis University School of Medicine, Saint Louis, MO 63110, USA.
  • 6 Department of Biochemistry & Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA.
  • 7 Division of Infectious Diseases, Allergy & Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA; Department of Molecular Microbiology & Immunology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA.
  • 8 Division of Infectious Diseases, Allergy & Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA; Department of Molecular Microbiology & Immunology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA. Electronic address: guangyong.peng@health.slu.edu.
PMID: 30344014 DOI: 10.1016/j.cmet.2018.09.020
Abstract

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.

Keywords

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

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