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| Status |
Public on Oct 27, 2022 |
| Title |
Immune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 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 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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| Overall design |
Comparison of transcriptional changes in pancreatic islet cells from anti-PD-L1 versus anti-CTLA-4 treated NOD mice.
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| Contributor(s) |
Perdigoto AL, Deng S, Du KC, Kuchroo M, Burkhardt DB, Tong A, Israel G, Robert ME, Weisberg SP, Kirkiles-Smith N, Stamatouli AM, Kluger HM, Quandt Z, Young A, Yang M, Mamula MJ, Pober JS, Anderson MS, Krishnaswamy S, Herold KC |
| Citation(s) |
35925682 |
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| Submission date |
Jul 20, 2022 |
| Last update date |
Oct 27, 2022 |
| Contact name |
Ana Luisa Perdigoto |
| E-mail(s) |
ana.perdigoto@yale.edu
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| Organization name |
Yale University
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| Street address |
300 George Street
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| City |
New Haven |
| State/province |
CT |
| ZIP/Postal code |
06520 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA860545 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE208644_processed_data.h5ad.gz |
66.5 Mb |
(ftp)(http) |
H5AD |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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