Protection against side effect
Stem cells prevent immunotherapy-related diabetes in mice.
Ekaterina Gugueva, PCR.news
In oncopatients receiving inhibitors of immune checkpoint, the development of type 1 diabetes may become a side effect. Japanese scientists have modeled immunotherapy-induced diabetes on mice and have shown that intravenous administration of mesenchymal stem cells protects pancreatic beta cells from death.
Tumor cells are able to "hide" from the body's immune system. One of the ways is the expression of so—called immune control points that prevent the attack of healthy tissues by immune cells. Thus, the PD-L1 molecule on the tumor cell membrane binds to the PD-1 receptor of the T-lymphocyte, which blocks its cytotoxic effect.
To combat some types of cancer, immune checkpoint inhibitors are used, triggering an antitumor immune response. However, recent studies show that such therapy is not harmless: in some patients, there is a breakdown of immune tolerance towards the cells of their own body. In particular, immunotherapy can lead to the development of type 1 diabetes mellitus (DM1).
Researchers from Osaka University (Japan) have proposed using mesenchymal stem cells (MSCs) to prevent DM1 in patients. It has previously been shown that the factors that secrete MSCs, including cytokines and exosomes, promote tissue regeneration, prevent fibrosis and modulate immune functions.
In the new work, scientists conducted experiments on mice. They found out that the blockade of PD-L1 by monoclonal antibodies causes massive infiltration of the islets of Langerhans by immune cells and a decrease in insulin secretion. This is due to the fact that in response to the inhibition of PD-1/PD-1L interaction, T-lymphocytes secrete interferon gamma, which attracts macrophages. In turn, macrophages expressing CXCL9 (a ligand to the CXCR3 receptor of T-lymphocytes) attract even more T-lymphocytes to the infiltration zone. Thus, immune cells have a cytotoxic effect on beta cells synthesizing insulin. Using the data obtained, the scientists created a mouse model of diabetes caused by the introduction of immune checkpoint inhibitors.
When MSCs obtained from human adipose tissue were injected into the caudal vein of mice with PD-L1 blockade, the number of T-lymphocytes and macrophages in the area of the islets of Langerhans decreased. Further analysis suggested that exosomes and cytokines secreted by MSCs inhibit the movement of immune cells into pancreatic tissue. This reduces the destruction of beta cells and, consequently, the likelihood of developing diabetes mellitus decreases.
In patients with the initial stage of type 1 diabetes, there is a therapeutic window — the moment when the number of enzymes of the exocrine part of the pancreas in the blood plasma increases, which indicates the beginning of an autoimmune process. It is during this period, according to the authors of the work, that MSCS therapy can be started. Cell therapy can reduce the likelihood of diabetes in cancer patients undergoing treatment with immune checkpoint inhibitors.
Article by Kawada-Horitani et al. Human adipose-derived mesenchymal stem cells prevent type 1 diabetes induced by immune checkpoint blockade is published in the journal Diabetologia.
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