Human adipose-derived mesenchymal stem cells prevent type 1 diabetes induced by immune checkpoint blockade

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.