T-Lymphocyte Infiltration to Islets in the Pancreas of a Patient Who Developed Type 1 Diabetes After Administration of Immune Checkpoint Inhibitors

Type 1 diabetes is a disease characterized by destruction of the β-cells in the pancreatic islets. The inhibitory receptor programmed cell death-1 (PD-1) and its ligands, programmed cell death ligand-1 (PD-L1) and PD-L2, have been shown to play an important role in regulating T-cell activation and peripheral tolerance. Inhibitors targeting PD-1 or PD-L1 are especially advantageous in the treatment of cancer. There are several reports where type 1 diabetes developed after administration of anti–PD-1 antibody (1). However, there is no report containing an immunohistochemical study of the pancreas. At the age of 55 years, a male patient underwent left radical nephrectomy for kidney cancer. At age 60, he was diagnosed with type 2 diabetes. Under the administration of vildagliptin, his hemoglobin A1c was maintained at ∼6% (41 mmol/mol). He was diagnosed with gallbladder metastasis of renal carcinoma at age 61 and underwent a cholecystectomy. Thereafter, he was diagnosed with renal carcinoma pancreatic metastasis, which increased in size, whereupon anti–CTLA4 antibody (ipilimumab) and anti–PD-1 antibody (nivolumab) combination therapy was started. Ipilimumab and nivolumab were administered four times over 2 months and nine times over 5 months, respectively. At age 63, 5 months after the start of administration, he developed diabetic ketoacidosis, his serum C-peptide was 1.8 ng/mL at that time, and insulin treatment was started. Anti–glutamic acid decarboxylase, anti–IA-2, and anti-IAA antibodies were negative, and his HLA haplotype was DRB1\*11:01-DQB1\*03:01 and DRB1\*09:01-DQB1\*03:03 . Two weeks after hospitalization, his serum C-peptide was <0.1 ng/mL. Thereafter, the combination …