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1252 Immune checkpoint inhibitor-induced diabetes mellitus comprises multiple clinical endotypes with distinct immunologic features
  1. Michelle Rengarajan1,2,
  2. Karina Ruiz Esteves1,
  3. Sergio Aguilar Fernandez1,2,
  4. Kaitlyn Shank3,
  5. Aaron Deutsch1,
  6. Leyre Zubiri1,
  7. Caitlin Colling1,
  8. Hoang Tran1,2,
  9. Alekhya Gunturi4,
  10. John McGuire1,2,
  11. Alice Tirard1,2,
  12. Benjamin Arnold1,
  13. Nandini Samanta1,2,
  14. Sidney Martin1,2,
  15. Katherine Perlman1,
  16. Tianqi Ouyang1,
  17. Alexander Gusev4,
  18. Dejan Juric1,
  19. Genevieve M Boland1,
  20. Meghan Sise1,
  21. Kerry Reynolds1 and
  22. Alexandra-Chloe Villani1,2
  1. 1Massachusetts General Hospital, Boston, MA, USA
  2. 2Broad Institute of Harvard and MIT, Cambridge, MA, USA
  3. 3Brigham and Women’s Hospital, Boston, MA, USA
  4. 4Dana Farber Cancer Institute, Boston, MA, USA


Background Immune 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.

Methods We 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 subsets associated with ICI-DM pathogenesis and heterogeneity.

Conclusions Our analysis identified several risk factors for ICI-DM that may identify patients at higher risk for ICI-DM. The results from our multi-modal strategy – combining clinical, genetic and translational approaches – to dissecting ICI-DM pathogenesis provides a roadmap on how to dissect the mechanistic determinants of ICI toxicities more broadly.

Ethics Approval This study was approved through the institutional review board of Mass General Brigham, protocol numbers: 2017P000501, 13–416 and 11–181. Participants who provided blood or serum gave their informed consent before taking part; for patients included exclusively in retrospective chart review, the IRB determined that individual informed consent was not needed.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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