Osaka, Japan – Immune checkpoint inhibitors are widely used to treat a variety of cancers; however, one serious side effect is the onset of type 1 diabetes. Now, researchers from Osaka University have discovered that stem cell therapy may protect against such side effects.
One strategy by which tumor cells evade recognition by the immune system is by upregulating factors that interfere with immune cell signaling – a process known as immune checkpoint. For example, the upregulation of programmed death-ligand 1 (PD-L1) leads to increased binding to its receptor (PD-1) on T cells of the immune system, inhibiting T cell activation. The therapeutic use of immune checkpoint inhibitors can reverse these effects, restoring immune system surveillance and tumor cell killing. However, these anti-cancer drugs are accompanied by autoimmune side effects, including the onset of type 1 diabetes.
Type 1 diabetes is a serious autoimmune disease that develops when the level of insulin produced by the islets of Langerhans in the pancreas drops below the required threshold, resulting in the body’s inability to control blood sugar levels. Such patients are dependent on insulin therapy. When insulin-producing cells are completely lost, the control of blood sugar levels becomes severely compromised, resulting in clinical complications, impaired quality of life, and a poor prognosis. Strategies for the prevention or cure of type 1 diabetes are currently lacking.
Mesenchymal stem cell (MSC) therapy is the most commonly used type of cell therapy. MSCs secrete factors that contribute to tissue regeneration, anti-fibrosis activity, and modulation of immune functions.
In the recent study at Osaka University, researchers showed that MSCs have therapeutic potential against immune-related adverse events. As Emi Kawada-Horitani, the lead author of the study, explains “We examined whether systemic MSC treatment could prevent the development of type 1 diabetes in a mouse model. First, we induced diabetes in the mice by administering a purified PD-L1 monoclonal antibody. Then, we injected human adipose-derived MSCs and analyzed immune cells in the pancreatic secretions.” Kawada-Horitani continues, “Inhibition of the PD-1/PD-L1 interaction with an anti-PD-L1 antibody resulted in a diabetes incidence of 64% among the mice, compared with 19% when the mice were also administered MSCs.”
Inhibition of the PD-1/PD-L1 interaction causes various changes in the immune system—most notably, the massive accumulation of immune cells (particularly macrophages) in the islets of Langerhans in the pancreas, disrupting insulin production.
“We found that MSCs effectively prevented this influx of immune cells,” corresponding author Shunbun Kita explains, “thereby avoiding the detrimental effects on pancreatic cells.” They further showed that MSCs secrete factors (such as exosomes) that protect the pancreatic cells against immune attack.
Their findings suggest that MSC transplantation can prevent the incidence of diabetes associated with immune checkpoint cancer therapy and is therefore worthy of consideration as a new type of adjuvant cell therapy.
The article, “Human adipose-derived mesenchymal stem cells prevent type 1 diabetes induced by immune checkpoint blockade,” was published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]) at DOI: https://doi.org/10.1007/s00125-022-05708-3
About Osaka University
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan's most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Method of Research
Subject of Research
Human adipose-derived mesenchymal stem cells prevent type 1 diabetes induced by immune checkpoint blockade
Article Publication Date
Osaka University have filed a patent claim regarding adiponectin-mediated stimulation of exosome production: Japanese Patent Application JP2017-131172 (inventors: SK et al). Osaka University and ROHTO Pharmaceutical have filed patents regarding improved MSC therapy for heart failure (JP2019-234288 [inventors: SK et al]), and the new MSC therapy for diabetes (JP2021-26666 [inventors: SK et al]). H. Nishida and YH are employees of ROHTO Pharmaceutical. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.