Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 6, Pages 1809-1814Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1417636112
Keywords
immune exhaustion; CD8T cells; antitumor immunity; tumor microenvironment; multifunctionality
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Funding
- Projects for Development of Innovative Research on Cancer Therapeutics by the Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Health and Labor Sciences Research Grants
- Research on Applying Health Technology in Japan
- Naito Foundation
- Takeda Science Foundation
- Secom Science and Technology Foundation
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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, TNF alpha, and IFN gamma. 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 mu M 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.
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