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Inflammatory Cell Infiltration into Islets without PD-L1 Expression is Associated with the Development of Immune Checkpoint Inhibitor-Related Type 1 Diabetes in Genetically Susceptible Patients

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posted on 2023-01-19, 18:58 authored by Satoshi Kawata, Junji Kozawa, Sho Yoneda, Yukari Fujita, Risa Kashiwagi-Takayama, Takekazu Kimura, Yoshiya Hosokawa, Megu Y Baden, Sae Uno, Rikako Uenaka, Kazuyuki Namai, Yoko Koh, Yoshito Tomimaru, Haruhiko Hirata, Motohide Uemura, Satoshi Nojima, Eiichi Morii, Hidetoshi Eguchi, Akihisa Imagawa, Iichiro Shimomura

  

Immune checkpoint inhibitors (ICIs) could cause type 1 diabetes (T1D). However, the underlying mechanism remains unclear. We immunohistochemically analyzed pancreatic specimens from 3 cases with ICI-related T1D, and their histopathological data were compared those from 3 patients who had received ICI therapy but did not develop T1D (non-T1D) and 7 normal glucose-tolerant subjects as controls. All ICI-related T1D patients had susceptible HLA haplotypes. In ICI-related T1D, the β‐cell area decreased and the α‐cell area increased compared to non-T1D and controls. The number of CD3-positive cells around islets increased in ICI-related T1D and non-T1D compared with controls, while the number of CD68-positive cells around islets increased in ICI-related T1D compared with non-T1D and controls. The expression ratios of PD-L1 on islets decreased in non-T1D and almost completely disappeared in ICI-related T1D, while PD-L1 expression was observed in most cells of pancreatic islets in controls. This study, therefore, indicates that ICI therapy itself could reduce PD-L1 expression on islets in all subjects, which may be related to β cell vulnerability. In addition, we showed that absence of PD-L1 expression on β cells, genetic susceptibility and infiltration of macrophages as well as T lymphocytes around islets might be responsible for T1D onset.

Funding

This study was supported in part by a Grant-in-Aid from the Japan Society for the Promotion of Science (Grant Number T19K180070).

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