A team of Okayama University scientists just helped shed light on an often proposed but poorly understood mechanism of metformin-dependent anticancer immunity. The study, published in (BMJ) Journal for ImmunoTherapy of Cancer, reveals that the antidiabetic drug metformin, used in the treatment of type 2 diabetes, induces the activation and proliferation of tumor-targeted CD8+ T cells. These data raise awareness of the potential use of metformin as an anti-tumor immune support drug in patients with cancer.
Cancer treatments have advanced significantly and, as with some viral infections, scientists hope that one day they will find a universal treatment that is effective against all the mutations and combinations of cancers that affect millions of people worldwide. Recent studies have shown that some drugs, such as the antidiabetic drug metformin, have anti-cancer properties. The use of metformin appears to enhance antitumor immunity. However, the underlying immunologic mechanisms are still poorly understood.
Metformin Stimulates CD8 Infiltrating T Cells
The Japanese team, therefore, studied how a specific subset of immune cells, called CD8+ infiltrating T cells (CD8TIL), which specifically attack cancer cells, behaves in response to metformin. The team conducted a series of experiments (in vitro) in tumor cell lines and (in vivo) in mice by genetically “inactivating” potential biomolecules that induce metformin-dependent anticancer immunity.
These experiments show that:
- Metformin induces the generation of reactive oxygen species in CD8TIL mitochondria and increases glycolysis,
These reactive oxygen species, mtROS, activate growth pathways in CD8TIL, thus allowing the proliferation of these immune cells.
- This mechanism is promoted by a transcription factor involved in the antioxidant stress response called Nrf,
Metformin does not cause any anticancer effect through “cell suicide” or apoptosis.
- On the contrary, metformin also induces a strong secretion of interferon-ɣ by CD8TILs, which alters the tumor microenvironment in a way that promotes cancer cell death.
The lead author of the study Professor Udono hopes that understanding the mechanisms by which metformin the antidiabetic drug works will inspire new treatments. These data, the author concludes, already strongly suggest the possibility of using metformin as a drug to boost anti-cancer immunity in cancer patients.
If the anti-cancer properties shown in this experiment on mice turn out to also apply to humans then we could see metformin used in the treatment of cancer within the next couple of years. Metformin is already approved for the treatment of diabetes and its safety profile is well understood.