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

Ana Luisa Perdigoto,¹ Songyan Deng,² Katherine C. Du,³ Manik Kuchroo,³ Daniel B. Burkhardt,³ Alexander Tong,³ Gary Israel,⁴ Marie E. Robert,⁵ Stuart P. Weisberg,⁶ Nancy Kirkiles-Smith,² Angeliki M. Stamatouli,⁷ Harriet M. Kluger,¹ Zoe Quandt,⁸ Arabella Young,⁹ Mei-Ling Yang,¹ Mark J. Mamula,¹ Jordan S. Pober,² Mark S. Anderson,⁸ Smita Krishnaswamy,³ and Kevan C. Herold²

Published August 4, 2022 - More info

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 (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 diabetes rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result 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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