TLR8-mediated metabolic control of human Treg function: a mechanistic target for cancer immunotherapy
| Autor: | Jian Ye, David A. Ford, Aiqin Gao, Eddy C. Hsueh, Fusheng Si, Katherine L. Sanders, Guangyong Peng, Xia Liu, James L. Edwards, Lingyun Li, Lan Huang, Daniel F. Hoft |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adoptive cell transfer Physiology Glucose uptake medicine.medical_treatment chemical and pharmacologic phenomena Breast Neoplasms Mice SCID Biology T-Lymphocytes Regulatory Article 03 medical and health sciences Mice 0302 clinical medicine Cancer immunotherapy Mice Inbred NOD Cell Line Tumor medicine Tumor Microenvironment Animals Humans Molecular Biology Melanoma Cellular Senescence Toll-like receptor Effector hemic and immune systems Cell Biology Immunotherapy TLR8 030104 developmental biology Glucose Toll-Like Receptor 8 Cancer research Female Reprogramming 030217 neurology & neurosurgery |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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