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

Immune checkpoint inhibitors (ICIs) could cause type 1 diabetes (T1D). However, the underlying mechanism remains unclear. We immunohistochemically analyzed pancreatic specimens from three individuals with ICI-related T1D, and their histopathological data were compared those from three patients who had received ICI therapy but did not develop T1D (non-T1D) and seven normal glucose-tolerant subjects as control subjects. 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 with non-T1D and control subjects. The number of CD3-positive cells around islets increased in ICI-related T1D and non-T1D compared with control subjects, while the number of CD68-positive cells around islets increased in ICI-related T1D compared with non-T1D and control subjects. The expression ratios of programmed death-ligand 1 (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 control subjects. 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. ARTICLE HIGHLIGHTS: Immune checkpoint inhibitors (ICIs) could cause type 1 diabetes (T1D). However, the underlying mechanism remains unclear. Pancreatic histological findings of ICI-related T1D patients were compared with those of patients who had received ICI therapy but did not develop T1D (non-T1D) and control subjects. Programmed death-ligand 1 expression on islets decreased in non-T1D and almost completely disappeared in ICI-related T1D, while it was observed in control subjects. Patients with ICI-related T1D had T1D-susceptible HLA haplotypes and islet inflammation. ICIs may decrease programmed death-ligand 1 expression on islets, and its absence and additional islet inflammation in genetically susceptible patients can lead to development of T1D.