Welcome! Here, we present our study of immunotherapy-related colitis (ircolitis).
Please read and cite our original research article:
- Thomas MF, Slowikowski K, Manakongtreecheep K, Sen P, Samanta N, Tantivit J, et al. Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis. Nature Medicine. 2024; 1–14. doi:10.1038/s41591-024-02895-x
BibTeX
@ARTICLE{Thomas2024-lk,
title = "{Single-cell transcriptomic analyses reveal distinct immune cell
contributions to epithelial barrier dysfunction in checkpoint
inhibitor colitis}",
author = "Thomas, Molly Fisher and Slowikowski, Kamil and
Manakongtreecheep, Kasidet and Sen, Pritha and Samanta, Nandini
and Tantivit, Jessica and Nasrallah, Mazen and Zubiri, Leyre and
Smith, Neal P and Tirard, Alice and Ramesh, Swetha and Arnold,
Benjamin Y and Nieman, Linda T and Chen, Jonathan H and
Eisenhaure, Thomas and Pelka, Karin and Song, Yuhui and Xu,
Katherine H and Jorgji, Vjola and Pinto, Christopher J and
Sharova, Tatyana and Glasser, Rachel and Chan, Puiyee and
Sullivan, Ryan J and Khalili, Hamed and Juric, Dejan and Boland,
Genevieve M and Dougan, Michael and Hacohen, Nir and Li, Bo and
Reynolds, Kerry L and Villani, Alexandra-Chloé",
journal = "Nature Medicine",
publisher = "Nature Publishing Group",
pages = "1--14",
abstract = "Immune checkpoint inhibitor (ICI) therapy has revolutionized
oncology, but treatments are limited by immune-related adverse
events, including checkpoint inhibitor colitis (irColitis).
Little is understood about the pathogenic mechanisms driving
irColitis, which does not readily occur in model organisms, such
as mice. To define molecular drivers of irColitis, we used
single-cell multi-omics to profile approximately 300,000 cells
from the colon mucosa and blood of 13 patients with cancer who
developed irColitis (nine on anti-PD-1 or anti-CTLA-4 monotherapy
and four on dual ICI therapy; most patients had skin or lung
cancer), eight controls on ICI therapy and eight healthy
controls. Patients with irColitis showed expanded mucosal Tregs,
ITGAEHi CD8 tissue-resident memory T cells expressing CXCL13 and
Th17 gene programs and recirculating ITGB2Hi CD8 T cells.
Cytotoxic GNLYHi CD4 T cells, recirculating ITGB2Hi CD8 T cells
and endothelial cells expressing hypoxia gene programs were
further expanded in colitis associated with anti-PD-1/CTLA-4
therapy compared to anti-PD-1 therapy. Luminal epithelial cells
in patients with irColitis expressed PCSK9, PD-L1 and
interferon-induced signatures associated with apoptosis,
increased cell turnover and malabsorption. Together, these data
suggest roles for circulating T cells and epithelial–immune
crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier
function and identify potential therapeutic targets for
irColitis. Single-cell multi-omic analysis of 300,000 cells from
29 patients representing peripheral immune cells and colon
mucosal immune, epithelial and mesenchymal cells reveals
crosstalk between circulating and tissue-resident immune cells
with epithelial cells in checkpoint inhibitor colitis and
identifies potential therapeutic targets.",
month = may,
year = 2024,
doi = "10.1038/s41591-024-02895-x",
issn = "1546-170X,1546-170X",
language = "en"
}
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Cell Clusters
Metadata variables and gene expression in two-dimensional embeddings. Tissue immune cells:
Tissue epithelial and mesenchymal nuclei:
Blood immune cells:
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Gene Contrasts
Differential expression statistics for all genes:
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This repository includes three main folders:
- The R source code for our analyses.
- The output results files from our analyses.
- The HTML, CSS, and Javascript source code for an interactive website to view the data and results.
The raw and processed scRNA-seq gene expression files are available at NCBI GEO GSE206301.
Sequencing reads are available at dbGAP accession phs003418.v1.p1.
Please see analysis/output/README.md for instructions on how to access the files.