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

• Published in: Diabetes (New York, N.Y.) Vol. 72; no. 4; pp. 511 - 519
• Main Authors: Kawata, Satoshi, Kozawa, Junji, Yoneda, Sho, Fujita, Yukari, Kashiwagi-Takayama, Risa, Kimura, Takekazu, Hosokawa, Yoshiya, Baden, Megu Y., Uno, Sae, Uenaka, Rikako, Namai, Kazuyuki, Koh, Yoko, Tomimaru, Yoshito, Hirata, Haruhiko, Uemura, Motohide, Nojima, Satoshi, Morii, Eiichi, Eguchi, Hidetoshi, Imagawa, Akihisa, Shimomura, Iichiro
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.04.2023
• Subjects: Apoptosis; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Beta cells; CD3 antigen; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Haplotypes; Humans; Immune Checkpoint Inhibitors; Immunology; Infiltration; Inflammation; Lymphocytes T; Macrophages; Pancreas; Pathophysiology; PD-L1 protein
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db22-0557

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.