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Attenuation of CD4+CD25+ Regulatory T Cells in the Tumor Microenvironment by Metformin, a Type 2 Diabetes Drug.

ABSTRACT: CD4+CD25+ regulatory T cells (Treg), an essential subset for preventing autoimmune diseases, is implicated as a negative regulator in anti-tumor immunity. We found that metformin (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 naïve 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.

SUBMITTER: Kunisada Y 

PROVIDER: S-EPMC5704053 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Attenuation of CD4<sup>+</sup>CD25<sup>+</sup> Regulatory T Cells in the Tumor Microenvironment by Metformin, a Type 2 Diabetes Drug.

Kunisada Yuki Y   Eikawa Shingo S   Tomonobu Nahoko N   Domae Shohei S   Uehara Takenori T   Hori Shohei S   Furusawa Yukihiro Y   Hase Koji K   Sasaki Akira A   Udono Heiichiro H  

EBioMedicine 20171016

CD4<sup>+</sup>CD25<sup>+</sup> regulatory T cells (Treg), an essential subset for preventing autoimmune diseases, is implicated as a negative regulator in anti-tumor immunity. We found that metformin (Met) reduced tumor-infiltrating Treg (Ti-Treg), particularly the terminally-differentiated CD103<sup>+</sup>KLRG1<sup>+</sup> population, and also decreased effector molecules such as CTLA4 and IL-10. Met inhibits the differentiation of naïve CD4<sup>+</sup> T cells into inducible Treg (iTreg) by  ...[more]

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