Immune cells and their inflammatory mediators modify β cells and cause checkpoint inhibitor-induced diabetes

Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (CPI-DM), which occurs preferentiall...

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Published inJCI insight Vol. 7; no. 17
Main Authors Perdigoto, Ana Luisa, Deng, Songyan, Du, Katherine C, Kuchroo, Manik, Burkhardt, Daniel B, Tong, Alexander, Israel, Gary, Robert, Marie E, Weisberg, Stuart P, Kirkiles-Smith, Nancy, Stamatouli, Angeliki M, Kluger, Harriet M, Quandt, Zoe, Young, Arabella, Yang, Mei-Ling, Mamula, Mark J, Pober, Jordan S, Anderson, Mark S, Krishnaswamy, Smita, Herold, Kevan C
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical investigation 08.09.2022
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Summary:Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (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 induced diabetes rapidly. RNA sequencing revealed that cytolytic IFN-γ+CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFN-γ and TNF-α and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFN-γ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFN-γ and anti-TNF-α prevented CPI-DM in anti-PD-L1-treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway resulted in transcriptional changes in β 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.
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ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.156330