Diabetes and other autoimmune endocrine diseases
Therapeutic agents targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1), known as checkpoint inhibitors (CPIs), have revolutionized cancer treatment by enhancing anti-tumor immune responses. While CPIs increase tumor destruction, they can cause a breakdown in self-tolerance resulting in autoimmune complications such as diabetes. The underlying mechanisms of CPI diabetes remain unknown. To understand β cell killing in patients treated with CPIs, we analyzed clinical and β cell changes in the setting of CPI. We observed elevated lipase and decreased pancreatic volume in patients with CPI diabetes consistent with exocrine pancreas inflammation. IFNy was produced by immune cells in response to human β cells in mixed lymphocyte reactions with anti-PD-1. We cultured human islets with IFNy and analyzed β cell responses by single cell RNAseq. RNAseq revealed higher expression of immune inhibitory ligands, PD-L1 and indoleamine 2,3-dioxygenase-1 (IDO1) in IFNγ treated cells, which was confirmed in cultured islets. PD-L1 expression was strongly correlated with STAT1 and inhibition of STAT1 eliminated upregulation of PD-L1 in β cells. We identified differentially expressed genes between PD-L1+ and PD-L1- β cells including those involved in regulation of apoptosis. Fas expression was higher in PD-L1+ versus PD-L1- β cells and increased apoptosis was observed in PD-L1+ cells. PD-L1 and IDO1 expression were observed in β cells in pancreatic tissue with known inflammation including a patient with CPI diabetes, suggesting a role for these molecules in vivo. Expression of immune inhibitor molecules seem to identify β cells under cellular stress that are susceptible to killing.