title: 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.affiliation: Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; and.
authors.forename: Shingo
authors.initials: S
authors.lastname: Eikawa
authors.affiliation: Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; and.
authors.forename: Mikako
authors.initials: M
authors.lastname: Nishida
authors.affiliation: Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; and.
authors.forename: Shusaku
authors.initials: S
authors.lastname: Mizukami
authors.affiliation: Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; and.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yamazaki
authors.affiliation: Faculty of Health and Welfare, Kawasaki University of Medical Welfare, Okayama 701-0193, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Nakayama
authors.affiliation: Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; and udono@cc.okayama-u.ac.jp.
authors.forename: Heiichiro
authors.initials: H
authors.lastname: Udono
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D019264:Adoptive Transfer; D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D008687:Metformin / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy*; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: CD8T cells; antitumor immunity; immune exhaustion; multifunctionality; tumor microenvironment