期刊
EBIOMEDICINE
卷 25, 期 -, 页码 154-164出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2017.10.009
关键词
Tumor immunity; Tumor microenvironment; Regulatory T cell (Treg); Glycolysis; mTOR
资金
- Japan Agency for Medical Research and Development (AMED)
- Projects for Development of Innovative Research on Cancer Therapeutics by Ministry of Education, Culture, Sports, Science and Technology Japan [15653356, 26116709]
- Secom Science and Technology Foundation
- Grants-in-Aid for Scientific Research [26116709, 16K18452, 17KT0055, 16K15666, 17H05789, 15H04747] Funding Source: KAKEN
CD4(+) CD25(+) regulatory T cells (Treg), an essential subset for preventing autoimmune diseases, is implicated as a negative regulator in anti-tumor immunity. Wefound thatmetformin (Met) reduced tumor-infiltrating Treg (Ti-Treg), particularly the terminally-differentiated CD103(+) KLRG1(+) population, and also decreased effector molecules such as CTLA4 and IL-10. Met inhibits the differentiation of naive CD4(+) T cells into inducible Treg (iTreg) by reducing forkhead box P3 (Foxp3) protein, caused by mTORC1 activation that was determined by the elevation of phosphorylated S6 (pS6), a downstream molecule of mTORC1. Rapamycin and compound C, an inhibitor of AMP-activated protein kinase (AMPK) restored the iTreg generation, further indicating the involvement of mTORC1 and AMPK. The metabolic profile of iTreg, increased Glut1-expression, and reduced mitochondrial membrane-potential and ROS production of Ti-Treg aided in identifying enhanced glycolysis upon Met-treatment. The negative impact of Met on Ti-Treg may help generation of the sustained antitumor immunity. (C) 2017 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
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