Human Leukocyte Antigens and Biomarkers in Type 1 Diabetes Mellitus Induced by Immune-Checkpoint Inhibitors

Abstract

Background: Type 1 diabetes mellitus induced by immune-checkpoint inhibitors (ICI-T1DM) is a rare critical entity. However, the etiology of ICI-T1DM remains unclear.Methods: In order to elucidate risk factors for ICI-T1DM, we evaluated the clinical course and immunological status of patients with ICI-T1DM who had been diagnosed during 2016 to 2021.Results: Seven of 871 (0.8%, six men and one woman) patients developed ICI-T1DM. We revealed that the allele frequencies of human leukocyte antigen (HLA)-DPA1*02:02 and DPB1*05:01 were significantly higher in the patients with ICI-T1DM In comparison to the controls who received ICI (11/14 vs. 10/26, <i>P</i>=0.022; 11/14 vs. 7/26, <i>P</i>=0.0027, respectively). HLA-DRB1*04:05, which has been found to be a T1DM susceptibility allele in Asians, was also observed as a high-risk allele for ICI-T1DM. The significance of the HLA-DPB1*05:01 and DRB1*04:05 alleles was confirmed by an analysis of four additional patients. The absolute/relative neutrophil count, neutrophils-lymphocyte ratio, and neutrophil-eosinophil ratio increased, and the absolute lymphocyte count and absolute/relative eosinophil count decreased at the onset as compared with 6 weeks before. In two patients, alterations in cytokines and chemokines were found at the onset.Conclusion: Novel high-risk HLA alleles and haplotypes were identified in ICI-T1DM, and peripheral blood factors may be utilized as biomarkers.