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Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1809-14. doi: 10.1073/pnas.1417636112. Epub 2015 Jan 26.

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

Author information

1
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; and.
2
Faculty of Health and Welfare, Kawasaki University of Medical Welfare, Okayama 701-0193, Japan.
3
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; and udono@cc.okayama-u.ac.jp.

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.

KEYWORDS:

CD8T cells; antitumor immunity; immune exhaustion; multifunctionality; tumor microenvironment

PMID:
25624476
PMCID:
PMC4330733
DOI:
10.1073/pnas.1417636112
[Indexed for MEDLINE]
Free PMC Article

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