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

Yuki Kunisada, Shingo Eikawa, Nahoko Tomonobu, Shohei Domae, Takenori Uehara, Shohei Hori, Yukihiro Furusawa, Koji Hase, Akira Sasaki, Heiichiro Udono

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
JournalEBioMedicine
DOIs
Publication statusAccepted/In press - 2017

Fingerprint

Tumor Microenvironment
T-cells
Metformin
Regulatory T-Lymphocytes
Medical problems
Type 2 Diabetes Mellitus
Tumors
AMP-Activated Protein Kinases
Pharmaceutical Preparations
Immunity
Neoplasms
Forkhead Transcription Factors
S 6
Molecules
Metabolome
Mitochondrial Membrane Potential
Glycolysis
Sirolimus
Interleukin-10
Autoimmune Diseases

Keywords

  • Glycolysis
  • MTOR
  • Regulatory T cell (Treg)
  • Tumor immunity
  • Tumor microenvironment

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Attenuation of CD4+CD25+ Regulatory T Cells in the Tumor Microenvironment by Metformin, a Type 2 Diabetes Drug. / Kunisada, Yuki; Eikawa, Shingo; Tomonobu, Nahoko; Domae, Shohei; Uehara, Takenori; Hori, Shohei; Furusawa, Yukihiro; Hase, Koji; Sasaki, Akira; Udono, Heiichiro.

In: EBioMedicine, 2017.

Research output: Contribution to journalArticle

Kunisada, Yuki ; Eikawa, Shingo ; Tomonobu, Nahoko ; Domae, Shohei ; Uehara, Takenori ; Hori, Shohei ; Furusawa, Yukihiro ; Hase, Koji ; Sasaki, Akira ; Udono, Heiichiro. / Attenuation of CD4+CD25+ Regulatory T Cells in the Tumor Microenvironment by Metformin, a Type 2 Diabetes Drug. In: EBioMedicine. 2017.
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