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.

Abstract

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.