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

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.

• Authors: Shingo Eikawa, Mikako Nishida, Shusaku Mizukami, Chihiro Yamazaki, Eiichi Nakayama, Heiichiro Udono
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 6 Pg. 1809-14 (Feb 10 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25624476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cytokines
• Metformin
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors)
• Adoptive Transfer
• Animals
• Antineoplastic Agents (immunology, pharmacology)
• Apoptosis (drug effects, immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology, transplantation)
• Cell Movement (immunology)
• Cytokines (immunology)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology, transplantation)
• Metformin (immunology, pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, SCID
• Neoplasms (drug therapy)
• Tumor Microenvironment (immunology)