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| Status |
Public on Nov 21, 2022 |
| Title |
Inhibition of IL-17A Protects against Thyroid Immune-related Adverse Events while Preserving Checkpoint Inhibitor Anti-tumor Efficacy [RNA-seq (murine)] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Checkpoint inhibitor (ICI) immunotherapy leverages the body’s own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. Here we present a novel mouse model in which checkpoint inhibitor therapy leads to multi-organ autoimmune infiltrates and show that activation and infiltration of Type 3 immune cells including IL17A+ RORgt+ CD4+ (T helper 17 or Th17) and gamma delta 17 (gdT17) T cells promote thyroid IrAE development. In parallel, Th17 and gdT17 cells were similarly expanded in cancer patients treated with ICI. Furthermore, antibody-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice. Finally, combination of IL-17A neutralization with ICI treatment in a mouse tumor model did not reduce ICI anti-tumor efficacy and indeed showed a trend toward enhancement. These studies suggest that targeting Th17 and gd17 function may reduce IrAE without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address IL17-mediated IrAE.
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| Overall design |
This dataset contains a total of 5 single cell transcriptomes from thyroid infiltrating CD45+ immune cells, pooled from 16 NOD.WT mice treated for 4 weeks with twice weekly intraperitoneal injections of anti-mouse PD-1 and anti-mouse CTLA-4 (10mg/kg/dose), or treated with isotype control antibodies (n=10 mice).
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| Contributor(s) |
Lechner MG, Cheng MI, Patel AY, Hoang AT, Yakobian N, Astourian M, Pioso MS, Rodriguez ED, McCarthy EC, Hugo W, Angell T, Drakaki A, Ribas A, Su MA |
| Citation(s) |
35817515 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| K08 DK129829 |
Mechanisms of Thyroid Autoimmunity in Checkpoint Immunotherapy |
UNIVERSITY OF CALIFORNIA LOS ANGELES |
Melissa G Lechner |
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| Submission date |
Jun 10, 2021 |
| Last update date |
Nov 21, 2022 |
| Contact name |
Melissa G Lechner |
| Organization name |
UCLA Geffen School of Medicine
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| Department |
Div of Endocrinology, Diabetes, and Metabolism
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| Lab |
Lechner/Su Labs
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| Street address |
10833 Le Conte Ave, CHS 57-154
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| City |
Los Angeles |
| State/province |
CA |
| ZIP/Postal code |
90095 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (5)
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| Relations |
| BioProject |
PRJNA736705 |
| SRA |
SRP323589 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE176561_mouse_irae_iso_integrated_counts.csv.gz |
20.1 Mb |
(ftp)(http) |
CSV |
| GSE176561_mouse_irae_iso_integrated_metadata.csv.gz |
327.5 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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