GSE208644
Immune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes
Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces DM rapidly. RNA sequencing revealed that cytolytic IFN?+ CD8+ T cells infiltrated islets with anti-PD-L1.  Changes in ß cells were predominantly driven by IFN? and TNFa and included induction of a novel ß cell population with transcriptional changes suggesting dedifferentiation. IFN? increased checkpoint ligand expression and activated apoptosis pathways in human ß cells in vitro. Treatment with anti-IFN? and anti-TNFa prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in ß cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication. Overall design: Comparison of transcriptional changes in pancreatic islet cells from anti-PD-L1 versus anti-CTLA-4 treated NOD mice.