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| Status |
Public on Jun 22, 2024 |
| Title |
Immunologic drivers of immune checkpoint inhibitor therapy myocarditis, fatality and anti-tumor response in cancer patients |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
Immune checkpoint inhibitors (ICIs) can offer remarkable benefits to patients with cancer, but these agents can cause morbid and potentially fatal immune-related adverse events (irAEs), the most lethal of which is ICI-related myocarditis (irMyocarditis). The pathogenesis of irMyocarditis and its relationship to anti-tumor immunity remain poorly understood. We sought to define how immune cell trafficking between heart, tumor and blood contributes to irMyocarditis pathogenesis and fatality by leveraging single-cell (sc)RNA-seq coupled with T cell receptor (TCR) sequencing, microscopy, and proteomics analysis of 28 irMyocarditis patients and 23 controls. Our analysis of ~284,360 cells from the heart and blood specimens identified enrichment of cytotoxic T-cell subsets, inflammatory macrophage subsets, conventional dendritic cells (cDCs), and fibroblasts in the heart that accompany the upregulation of potentially targetable, pro-inflammatory transcriptional programs. Expanded TCR clones enriched in irMyocarditis are largely distinct from those in paired tumors, suggesting distinct mechanisms between anti-tumor immune response and irMyocarditis. We also identified circulating biomarkers of fatality, including decreased circulating CD4+ T cells, decreased cDCs, and the presence of cardiac-expanded TCRs in a circulating, cycling CD8+ T cell population. Collectively, these findings highlight critical biology driving disease pathogenesis and nominate putative biomarkers and tailored therapeutic interventions for patients with irMyocarditis.
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| Overall design |
Heart samples were taken through endomyocardial biopsies or autopsy from patients receiving an ICI for cancer. Additionally, patients had PBMCs collected at multiple timepoints through their course of treatment. Samples were then used for scRNA-seq.
>>>Submitter states: The raw data will be submitted via dbGaP as it needs to be under controlled access.<<<
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| Contributor(s) |
Smith NP, Kernin IJ, Blum SM, Zlotoff DA, Villani A |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Mar 30, 2023 |
| Last update date |
Jun 24, 2024 |
| Contact name |
Neal Patrick Smith |
| E-mail(s) |
nsmith19@mgh.harvard.edu
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| Organization name |
Massachusetts General Hospital
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| Street address |
149 13th Street
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| City |
Charlestown |
| State/province |
MA |
| ZIP/Postal code |
02129 |
| Country |
USA |
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| Platforms (2) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (75)
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| Relations |
| BioProject |
PRJNA950416 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE228597_RAW.tar |
3.2 Gb |
(http)(custom) |
TAR (of CSV, H5, TSV) |
| GSE228597_cite_info.csv.gz |
5.9 Kb |
(ftp)(http) |
CSV |
| GSE228597_combined_pbmc_data.h5ad.gz |
3.0 Gb |
(ftp)(http) |
H5AD |
| GSE228597_combined_tissue_data.h5ad.gz |
574.9 Mb |
(ftp)(http) |
H5AD |
| GSE228597_hashing_info.csv.gz |
708 b |
(ftp)(http) |
CSV |
| Raw data not provided for this record |
| Processed data provided as supplementary file |
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