Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis
Creators
- Molly Fisher Thomas1, 2, 3, 4, 5
- Kamil Slowikowski1, 2, 3, 4
- Kasidet Manakongtreecheep1, 2, 3
- Pritha Sen1, 2, 3, 4, 6
- Nandini Samanta1, 2, 3
- Jessica Tantivit1, 2, 3
- Mazen Nasrallah1, 2, 3, 4, 7
- Leyre Zubiri2, 4
- Neal P. Smith1, 2, 3
- Alice Tirard1, 2, 3
- Swetha Ramesh1, 2, 3
- Benjamin Y. Arnold1, 2, 3
- Linda T. Nieman2
- Jonathan H. Chen2, 3, 4, 8
- Thomas Eisenhaure3
- Karin Pelka2, 3, 4
- Yuhui Song2
- Katherine H. Xu2
- Vjola Jorgji2, 8
- Christopher J. Pinto2, 9
- Tatyana Sharova9
- Rachel Glasser5
- PuiYee Chan2, 4
- Ryan J. Sullivan2, 4
- Hamed Khalili3, 4, 5
- Dejan Juric2, 3, 4
- Genevieve M. Boland2, 4, 10
- Michael Dougan4, 5
- Nir Hacohen2, 3, 4
- Bo Li1, 3, 11
- Kerry L. Reynolds2, 4
- Alexandra-Chloé Villani1, 2, 3, 4, 7
- 1. Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- 2. Massachusetts General Hospital, Cancer Center, Boston, MA, USA
- 3. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- 4. Harvard Medical School, Boston, MA, USA
- 5. Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- 6. Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- 7. Division of Rheumatology, North Shore Physicians Group, Department of Medicine, Mass General Brigham Healthcare Center, Lynn, MA, USA
- 8. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
- 9. Clinical Research Center, Massachusetts General Hospital, Boston, MA, USA
- 10. Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
- 11. Current address: Genentech, 1 DNA Way, South San Francisco, CA, 94080
Description
Abstract
Therapeutic immune checkpoint blockade has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). To define molecular drivers of irColitis, we profiled ~300,000 cells from the colon mucosa and blood of 29 patients and controls. Patients with irColitis showed expanded mucosal Tregs, ITGAEHi CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs, and circulating ITGB2Hi CD8 T cells recruited by ICAM and CXCR3 ligands. Cytotoxic GNLYHi CD4 T cells, ITGB2Hi CD8 T cells from circulation, and endothelial cells associated with hypoxia gene programs were further expanded in colitis associated with anti-PD-1/CTLA-4 compared to anti-PD-1 therapy. Luminal epithelial cells in irColitis patients expressed PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover, and malabsorption. Together, we highlight novel roles for circulating T cells and epithelial-immune crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and nominate novel irColitis therapeutic targets.
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This Zenodo page provides download links for the code we developed for the analysis and the website, as well as the files containing analysis results.
To get started, download the zip file shown below. For analysis results, look for the analysis/output
folder and read our tutorial for how to access the expression data in R and Python.
The v3 release adds cell cluster marker data for Luoma CD4 T cells and Luoma CD8 T cells to the file analysis/output/de-ova.tsv.gz
.
Files
villani-lab/ircolitis-v3.zip
Files
(321.4 MB)
Name | Size | Download all |
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Additional details
Funding
Software
- Repository URL
- https://github.com/villani-lab/ircolitis
- Programming language
- R