DOI: 10.5061/dryad.xwdbrv1fh
title: Human adipose-derived mesenchymal stem cells prevent type 1 diabetes induced by immune checkpoint blockade

description: Aims/hypothesis Immunomodulators blocking cytotoxic
 T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death
 protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have improved the
 treatment of a broad spectrum of cancers. These immune checkpoint
 inhibitors (ICIs) reactivate the immune system against tumour cells but
 can also trigger autoimmune side effects, including type 1 diabetes.
 Mesenchymal stem cell (MSC) therapy is the most prevalent cell therapy,
 with tissue-regenerating, anti-fibrosis and immunomodulatory functions
 provided by the secretome of the cells. Here, we examined whether systemic
 MSC treatment could prevent the development of type 1 diabetes in a NOD
 mouse model. Methods The purified PD-L1 monoclonal antibody was
 administered to induce diabetes in male NOD mice which normally do not
 develop diabetes. Human adipose-derived MSCs were administered by tail
 vein injections. T cells, macrophages and monocyte-derived macrophages
 expressing C-X-C motif chemokine ligand 9 (CXCL9) in pancreatic sections
 of NOD mice and a cancer patient who developed diabetes following the ICI
 treatments were analysed by immunofluorescence. Tissue localisation of the
 injected MSCs, plasma exosome levels and plasma cytokine profiles were
 also investigated. Results PD-1/PD-L1 blockade induced diabetes in 16 of
 25 (64%) NOD mice which received anti-PD-L1 mAb without hMSCs [MSC(−)],
 whereas MSC administration decreased the incidence to four of 21 (19%) NOD
 mice which received anti-PD-L1 mAb and hMSCs [MSC(+)]. The PD-1/PD-L1
 blockade significantly increased the area of CD3-positive T cells
 (6.2-fold) and Macrophage-2 (Mac-2) antigen (2.5-fold)- and CXCL9
 (40.3-fold)-positive macrophages in the islets. MSCs significantly reduced
 T cell (45%) and CXCL9-positive macrophage (67%) accumulation in the
 islets and the occurrence of diabetes. The insulin content (1.9-fold) and
 islet beta cell area (2.7-fold) were also improved by MSCs. T cells and
 CXCL9-positive macrophages infiltrated into the intricate gaps between the
 beta cells in the islets by PD-1/PD-L1 blockade. Such immune cell
 infiltration was largely prevented by MSCs. The most striking difference
 was observed in the CXCL9-positive macrophages, which normally did not
 reside in the beta cell region in the islets but abundantly accumulated in
 this area after PD-1/PD-L1 blockade and were prevented by MSCs. The
 CXCL9-positive macrophages were also observed in the islets of a cancer
 patient who developed diabetes following the administration of ICIs but
 little was observed in a control patient. Mechanistically, the injected
 MSCs accumulated in the lung but not in the pancreas and strongly
 increased plasma exosome levels and changed plasma cytokine profiles.
 Conclusions/interpretation Our results suggest that MSCs can prevent the
 incidence of diabetes associated with immune checkpoint cancer therapy and
 may be worth further consideration for new adjuvant cell therapy. Data
 availability All datasets were deposited to DOI
 https://doi.org/10.5061/dryad.xwdbrv1fh.