Immune-mediated antitumor effect by type 2 diabetes drug, metformin

Shingo Eikawa, Mikako Nishida, Shusaku Mizukami, Chihiro Yamazaki, Eiichi Nakayama, Heiichiro Udono

Research output: Contribution to journalArticle

167 Citations (Scopus)

Abstract

Metformin, a prescribed drug for type 2 diabetes, has been reported to have anti-cancer effects; however, the underlying mechanism is poorly understood. Here we show that this mechanism may be immune-mediated. Metformin enabled normal but not T-cell-deficient SCID mice to reject solid tumors. In addition, it increased the number of CD8+ tumor-infiltrating lymphocytes (TILs) and protected them from apoptosis and exhaustion characterized by decreased production of IL-2, TNFα, and IFNγ. CD8+ TILs capable of producing multiple cytokines were mainly PD-1-Tim-3+, an effector memory subset responsible for tumor rejection. Combined use of metformin and cancer vaccine improved CD8+ TIL multifunctionality. The adoptive transfer of antigen-specific CD8+ T cells treated with metformin concentrations as low as 10 μM showed efficient migration into tumors while maintaining multifunctionality in a manner sensitive to the AMP-activated protein kinase (AMPK) inhibitor compound C. Therefore, a direct effect of metformin on CD8+ T cells is critical for protection against the inevitable functional exhaustion in the tumor microenvironment.

Original languageEnglish
Pages (from-to)1809-1814
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number6
DOIs
Publication statusPublished - Feb 10 2015

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Metformin
Type 2 Diabetes Mellitus
Tumor-Infiltrating Lymphocytes
Pharmaceutical Preparations
T-Lymphocytes
Neoplasms
CD8 Antigens
Cancer Vaccines
AMP-Activated Protein Kinases
Tumor Microenvironment
SCID Mice
Adoptive Transfer
Protein Kinase Inhibitors
Interleukin-2
Apoptosis
Cytokines

Keywords

  • Antitumor immunity
  • CD8T cells
  • Immune exhaustion
  • Multifunctionality
  • Tumor microenvironment

ASJC Scopus subject areas

  • General

Cite this

Immune-mediated antitumor effect by type 2 diabetes drug, metformin. / Eikawa, Shingo; Nishida, Mikako; Mizukami, Shusaku; Yamazaki, Chihiro; Nakayama, Eiichi; Udono, Heiichiro.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 6, 10.02.2015, p. 1809-1814.

Research output: Contribution to journalArticle

Eikawa, Shingo ; Nishida, Mikako ; Mizukami, Shusaku ; Yamazaki, Chihiro ; Nakayama, Eiichi ; Udono, Heiichiro. / Immune-mediated antitumor effect by type 2 diabetes drug, metformin. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 6. pp. 1809-1814.
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