Immune-mediated antitumor effect by type 2 diabetes drug, metformin
| Autor: | Shusaku Mizukami, Heiichiro Udono, Mikako Nishida, Shingo Eikawa, Chihiro Yamazaki, Eiichi Nakayama |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
Adoptive cell transfer chemical and pharmacologic phenomena Antineoplastic Agents Apoptosis Mice SCID AMP-Activated Protein Kinases CD8-Positive T-Lymphocytes Biology Mice Lymphocytes Tumor-Infiltrating Immune system Cell Movement Neoplasms Internal medicine Tumor Microenvironment medicine Animals Mice Inbred BALB C Tumor microenvironment Multidisciplinary AMPK Biological Sciences Adoptive Transfer Metformin Mice Inbred C57BL Endocrinology Cancer research Cytokines Tumor necrosis factor alpha Cancer vaccine CD8 medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 112:1809-1814 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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