Abstract | AIMS/HYPOTHESIS: 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 few CXCL9-positive macrophages were 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.
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Authors | Emi Kawada-Horitani, Shunbun Kita, Tomonori Okita, Yuto Nakamura, Hiroyuki Nishida, Yoichi Honma, Shiro Fukuda, Yuri Tsugawa-Shimizu, Junji Kozawa, Takaaki Sakaue, Yusuke Kawachi, Yuya Fujishima, Hitoshi Nishizawa, Miyuki Azuma, Norikazu Maeda, Iichiro Shimomura |
Journal | Diabetologia
(Diabetologia)
Vol. 65
Issue 7
Pg. 1185-1197
(07 2022)
ISSN: 1432-0428 [Electronic] Germany |
PMID | 35511238
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2022. The Author(s). |
Chemical References |
- Antibodies, Monoclonal
- B7-H1 Antigen
- Immune Checkpoint Inhibitors
- Programmed Cell Death 1 Receptor
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Topics |
- Animals
- Antibodies, Monoclonal
- B7-H1 Antigen
(metabolism)
- Diabetes Mellitus, Type 1
(metabolism)
- Humans
- Immune Checkpoint Inhibitors
- Male
- Mesenchymal Stem Cells
(metabolism)
- Mice
- Mice, Inbred NOD
- Neoplasms
(metabolism)
- Programmed Cell Death 1 Receptor
(metabolism)
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