1252 Immune checkpoint inhibitor-induced diabetes mellitus comprises multiple clinical endotypes with distinct immunologic features

BackgroundImmune checkpoint inhibitor-induced diabetes mellitus (ICI-DM) is a rare adverse effect of ICI therapy, presumably caused by immune-mediated destruction of insulin-producing pancreatic β-cells. ICI-DM carries significant mortality risk and markedly disrupts patients’ quality of life. Importantly, ICI-DM is a valuable model to examine how ICI toxicities relate to spontaneous autoimmunity at the clinical, genetic, and immunological level, and to dissect how distinct clinical endotypes of an ICI-toxicity may differ mechanistically.MethodsWe combined: (1)retrospective analysis of data from 14,440 ICI-treated patients, (2)genetic analysis from >1000 of these ICI-treated patients, and (3)high-definition multimodal analysis of circulating immune cells at ICI-DM diagnosis from 11 patients, to comprehensively characterize ICI-DM. In (1), we identified 65 cases of ICI-DM among 14,440 patients treated with ICI in 2010–2022 within our multi-centered academic hospital system, which we further stratified by β-cell function (i.e., insulin production) and by the presence of type 1 diabetes (T1D)-specific autoantibodies for further clinical phenotyping. In (2), we imputed germline genotype using the OncoPanel data from patient tumors and calculated a composite T1D polygenic risk score for patients with and without ICI-DM. Finally in (3), we performed single-cell multi-omics analyses on >150,000 circulating immune cells isolated from these ICI-DM patients and compared these results with patients with newly diagnosed T1D.Results Risk factors: The incidence of ICI-DM in our cohort was 0.45%, significantly increased in patients with pre-existing T2D (OR 5.8) or treated with combination ICI (OR 2.5). Patients with ICI-DM had a significantly higher T1D composite genetic risk compared to ICI-treated patients without ICI-DM (OR 6.4). Clinical endotypes: We identified three distinct ICI-DM groups, including patients with (1)preserved insulin production (14% of ICI-DM, referred to as β+), (2, 3)loss of insulin production (β-) with elevated (40%, Ab+β-) or absent (45%, Ab-β-) islet-specific autoantibodies (40%, Ab+β-) islet-specific autoantibodies. Among these groups, Ab+β- presented with fulminant ICI-DM, with high rates of life-threatening complications (63%), whereas presentation of both β+ and Ab-β- were more protracted. Immunological phenotyping: We will present our paired single-cell RNA sequencing and T-cell receptor analysis examining distinct circulating T cell sub