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Introduction /               

Immune checkpoint inhibitors (ICIs), the stars of the anticancer world, have shown excellent efficacy in the treatment of many types of cancers and have brought new hope to many cancer patients since their inception.

However, like other anti-tumour drugs, immune checkpoint inhibitors, while exerting anti-tumour effects, are also accompanied by the occurrence of immunotherapy-associated adverse effects (irAE), which may cause side effects such as autoimmune diseases, and one of the serious side effects is that they may lead to the occurrence of type 1 diabetes.

 

01 Mesenchymal Stem Cells Reduce Immune-Check Inhibitors

induced - type 1 diabetes incidence

In an article published in SpringerLink May 2022 titled "Human adipose-derived mesenchymal stem cells prevent type 1 diabetes induced by immune checkpoint blockade, Researchers constructed a mouse model of type 1 diabetes induced by immunosuppression and demonstrated that MSCs significantly reduced the incidence of type 1 diabetes and acted to protect pancreatic β-cells by analysing the state of the mice after injection of MSCs.

 

Figure 1. from SpringerLink

 

The researchers randomly divided the NOD mice into three groups: a healthy control group, a group injected with a monoclonal antibody against PD-L1 and mesenchymal stem cells (MSC+), and a group injected with only a monoclonal antibody against PD-L1 (MSC-), and subjected them to a 16-day experiment after they had reached a relatively average value of both blood glucose and body weight at the start of the experiment.

 

Figure 2. from the literature [1]

 

其中MSC+组每间隔2-3天进行一次间充质干细胞的尾部静脉注射，MSC+和MSC-组均在第0、2、5、7、9、12天注射抗PD-L1单克隆抗体。并在0、2、5、7、9、12、14天从尾部静脉测量3组小鼠的血糖。

 

Figure 3. from the literature [1]

 

There were 25 mice in the MSC- group, of which 16 mice developed type 1 diabetes, while only 4 out of 21 mice in the MSC+ group injected with MSC developed type 1 diabetes, and blood glucose measurements showed that the average blood glucose in the MSC+ group was significantly lower than that in the MSC- group. This demonstrated that MSC significantly reduced the incidence of type 1 diabetes caused by immune checkpoint inhibitors.

 

02 MSCs play a protective role for pancreatic islets

 

On day 16 of the experiment, the researchers sectioned the pancreas of the mice and performed H&E staining and immunostaining to observe the status of the pancreatic islets, as well as assessing the islet area and measuring the insulin content.

 

Figure 4. from the literature [1]

 

The results showed that the same typical round islets as in the control group were present in the MSC+ group, while obvious phenomena such as deformation and absence of islets were observed in the MSC- group. The area of residual pancreatic islet β-cells in pancreatic sections was quantified, and the area in the MSC+ group was significantly higher than that in the MSC- group; moreover, the results of insulin content assay showed that the insulin content in the MSC+ group was also slightly higher than that in the MSC- group. This phenomenon confirms that MSCs play a protective role for pancreatic islets and pancreatic β-cells.

The researchers subsequently visualised immunofluorescence images of T cells (CD3-positive), Mac-2-positive macrophages, CXCL9-positive macrophages, and β cells (insulin-positive) in pancreatic islets.

 

Figure5. from the literature [1]

 

In comparison to the control group, a reduction in beta cell area (red) can be observed in the MSC- group, with a large accumulation of T cells (dark blue) and macrophages (green) in the pancreatic islets in the beta cell interstitial space, and the entire beta cell area of the pancreatic islets is invaded by T cells leading to deformities, which proves that immune cells are destroying the beta cells and reducing the level of insulin in the bloodstream, therefore contributing to the onset of type 1 diabetes mellitus. Whereas the images of the MSC+ group showed that due to the influence of MSCs, T cells and macrophages in the pancreatic islets were prevented from clustering in the β-cell clusters, allowing the β-cells to maintain a relatively healthy state.

 

03 Possible mechanisms of action of MSCs

 

It is worth mentioning that the researchers stained the MSCs with PKH in order to observe the fate of the MSCs injected into the mice, and the staining results showed that the MSCs were present in large numbers in the lung tissues, whereas no PKH-labelled MSCs were found in the pancreas, spleen or liver.

 

Figure 6. from the literature [1]

 

This finding prompted the researchers to think that MSCs may be affecting other organs by secreting cytokines and exosomes. The plasma of the mice 4 hours after MSC injection was then analysed for protein levels to assess the level of exosomes in the plasma.

 

Figure 7. from the literature [1]

 

The exosome markers CD63 and MFG-E8 were stained using human-specific antibodies, so the significantly elevated levels in the MSC+ group indicated the presence of MSCs-derived exosomes in the plasma, while the elevated levels of the exosome markers Alix and syntenin indicated that the plasma levels of exosomes were significantly increased in mice after MSC injection. These evidences led the researchers to conclude that MSCs most likely act through the secretion of exosomes, thereby protecting organs from various diseases.

 

04 Conclusion

 

ICI-associated type 1 diabetes is a less common but life-threatening side effect of cancer immunotherapy, and this study demonstrated that repeated use of immune checkpoint inhibitors leads to invasion of the pancreatic islets by immune cells, decreasing the area of β-cells in the pancreas and insulin levels. Injections of MSCs, on the other hand, effectively blocked the influx of immune cells, thereby avoiding adverse effects on pancreatic cells and significantly reducing the chances of developing type 1 diabetes. Although the entire study was centred around type 1 diabetes, the findings also demonstrate that the effects of MSCs may not be limited to the pancreas, and therefore more clinical applications of this MSC-assisted therapy should be tested so that more patients can benefit from it.