Metformin confers anti-tumor immunity by reactivating exhausted CD8T lymphocytes

Metformin confers anti-tumor immunity by reactivating exhausted CD8T lymphocytes
Mice inoculated with melanoma cells (MO5 expressing OVA) were treated w/o metformin(Met) from day 7, as indicated by the shadowed rectangle, and tumor growth was monitored. Metfromin treated mice showed significant inhibition of tumor growth.

Anti-cancer effect of tumor infiltrating CD8+T lymphocyte (CD8TIL) is suppressed by interaction between immune-checkpoint molecules such as PD-1 and CTLA-4 expressed on CD8TIL and their ligands expressed on cancer cells, which is referred to as immune-exhaustion. Cancer immunotherapy with antibody-mediated, immune-checkpoint blockade is now promising in preventing advanced melanoma and non small cell lung carcinoma (NSCLC). Such antibody-mediated immunotherapy, however, faces their enormous financial problem and significant side effects like autoimmune diseases.

On the other hand, metformin, a safe and low cost drug prescribed for patients with type 2 diabetes, has been recognized to have anti-cancer effect. We found that CD8TIL is a target of metformin. CD8TIL inevitably undergoes immune-exhaustion, characterized by diminished production of multiple cytokines such as IL-2, TNFα and IFNγ, followed by elimination with apoptosis. Metformin is able to counter the state. Metformin, thus, blocked immune exhaustion within .

Mice administered metformin by free drinking water, showed significant tumor growth inhibition in 6 distinct tumor models and CD8TIL becomes resistant against apoptosis, furthermore, it begins to produce multiple cytokines. Blood concentration of metformin in those mice is almost comparable to that of type 2 diabetes patients who are taking metformin daily. Therefore, along with other cancer immunotherapies, treatment of cancer patients with may significantly improve the efficacy and have a great benefit for their prognosis.

Metformin confers anti-tumor immunity by reactivating exhausted CD8T lymphocytes
On days 7, 10 and 13, TILs were recovered from tumor masses, and CD8+ TILs were examined for Kb-OVA257–264 and Kb-TRP2180–188 tetramer binding (n = 7–13) by flow cytometry analysis. The population of CD8+ TILs specific for either antigen, OVA257–264 or TRP2180–188, was significantly increased in metformin treated mice (+), compared with non-treated mice (-). The accumulation of antigen specific of CD8+ TILs is caused by inhibition of apoptosis by metformin treatment.

More information: Shingo Eikawa et al. Immune-mediated antitumor effect by type 2 diabetes drug, metformin, Proceedings of the National Academy of Sciences (2015). DOI: 10.1073/pnas.1417636112

Provided by Okayama University
Citation: Metformin confers anti-tumor immunity by reactivating exhausted CD8T lymphocytes (2016, February 24) retrieved 8 December 2023 from
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