189-OR: Immune-Profiling of Pancreatic Tissue Affected by Immune Checkpoint Inhibitor–Induced Diabetes (CPI-D)

Intro: CPI-D is a rare but morbid side effect of cancer immunotherapy. Limited availability of affected pancreatic tissue is a critical barrier to understanding its molecular and cellular underpinnings.

Methods: We procured pancreatic tissue and blood from a 68-year-old man who had developed CPI-D during immunotherapy for metastatic melanoma and was then diagnosed with pancreatic cancer, leading to partial pancreatectomy. Tumor-uninvolved pancreatic tissue was examined using H&E, IHC (including an advanced form of IHC, CODEX) , and single cell RNA sequencing (scRNAseq) .

Results: The pancreatic tissue harbored few islets, which were identified by the presence of glucagon given lack of insulin production. The islets were surrounded by immune cells that were composed primarily of B cells, CD4⁺ T and CD8⁺ T cells, some of which expressed PD-1, as demonstrated by scRNAseq and CODEX, which also identified FOXP3⁺ regulatory T cells that highly expressed OX40. Discussion: We report the first analysis of CPI-D-affected pancreatic tissue at single cell resolution, combining scRNAseq and spatial imaging to provide evidence for an autoimmune etiology for CPI-D. The pancreatic immune composition shared similarities with tertiary lymphoid organs (TLOs) , as previously observed in the pancreas of T1D patients. The presence of PD-1 was further notable, given the specific association of CPI-D with PD-1 inhibitor therapy. Despite the presence of B cells, this patient was negative for typical T1D autoantibodies (GAD65, insulin, IC512, zinc transporter 8) , which occur in approximately half of CPI-D cases.

Conclusion: Profiling the pancreatic histology and immune composition in a patient with CPI-D offered a rare opportunity to explore pathogenesis.This portion of CPI-D affected pancreas was significantly depleted of insulin expressing islets and displayed an immune cell infiltrate reminiscent of T1D in composition and topology, supporting that CPI-D is an autoimmune state.