May 26, 2024

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Metformin Helps Immune System Better Recognize Cancer Cells

Metformin Helps Immune System Better Recognize Cancer Cells



Metformin Helps Immune System Better Recognize Cancer Cells

Metformin, a first-line drug for treating type 2 diabetes that reduces blood sugar levels by inhibiting glucose production in the liver, is one of the most commonly prescribed drugs worldwide, with over a hundred million people taking it. Despite being an old drug, research on metformin has never ceased, and interest in its effects continues to grow. Metformin has been found not only to lower blood sugar levels but also to have weight-loss effects. In August 2023, a study published in Nature revealed that metformin enhances the killing ability of γδT cells against cancer cells, pointing to a new direction for cancer immunotherapy.

Recently, researchers from the University of Helsinki in Finland published a study titled “Respiratory complex I regulates dendritic cell maturation in an explant model of the human tumor immune microenvironment” in the Journal for ImmunoTherapy of Cancer.

The study found that metformin can activate the immune cells in the human body, particularly evident in dendritic cells. Metformin promotes the metabolism of dendritic cells, making them more active and enhancing their immune response against cancer cells. This discovery contributes to the development of cancer therapies based on the combined effects of metformin and the activation of the immune system.

 

Metformin Helps Immune System Better Recognize Cancer Cells

 

 

The team had previously developed a method to cultivate three-dimensional human breast cancer tissues, known as patient-derived explant cultures (PDEC). PDECs are directly derived from tissues surgically removed from patients, containing both living tumor cells and immune cells infiltrating the tumor tissue. This method allows for the study of the effects of drugs on both tumor cells and immune cells in the tumor tissue of real human patients, revealing the mechanisms of action of therapeutic drugs in the context of human tumor tissues.

Previous studies have shown that in a mouse model of breast cancer with high expression of the oncogene MYC, there is a particular susceptibility to combination treatment with Venetoclax and metformin (Venetoclax is a Bcl-2 inhibitor used to treat leukemia and other cancers). Furthermore, the combination treatment of Venetoclax and metformin (VeM) can inhibit tumor growth in mice, and when further combined with a PD-1 inhibitor, it can induce sustained therapeutic effects. The anticancer effect of VeM combination therapy raises an interesting question: does metformin act solely by promoting cancer cell death, or does it also directly regulate the immune response in some way?

In this study, the researchers further explored the effects of metformin on human breast cancer tissue samples using patient-derived explant cultures (PDEC), providing a unique method to study the effects of Venetoclax and metformin on both tumor cells and tumor-resident immune cells under ex vivo conditions.

The study found for the first time that PDECs can maintain the immune composition and baseline immune activity of primary breast tumors. Additionally, the study demonstrated that the cytolytic activity of T cells in PDECs can be activated by a direct T cell activator (anti-CD3/CD28/CD2), but not through the PD-1/PD-L1 mechanism. As observed previously in mice, Venetoclax reduced the tumor-infiltrating lymphocytes in PDECs, which metformin could not counteract.

Unexpectedly, the study found that metformin promotes the maturation of human dendritic cells (DCs) by inhibiting respiratory chain complex I, altering immune cell metabolism. Metformin-induced maturation of dendritic cells can trigger the proliferation of CD4+ T cells, suggesting that inhibiting complex I of the respiratory chain or other components of mitochondrial respiration could serve as a potential new strategy to enhance cancer immunotherapy.

Article links:

https://www.nature.com/articles/s41586-023-06482-x

https://jitc.bmj.com/content/12/4/e008053

Metformin Helps Immune System Better Recognize Cancer Cells

(source:internet, reference only)


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