Altered interactions between circulating and tissue-resident CD8 T cells with the colonic mucosa define checkpoint inhibitor colitis

Molly Fisher Thomas^1-5*†, Kamil Slowikowski^1-4*†, Kasidet Manakongtreecheep^1-3, Pritha Sen^1-4,6, Nandini Samanta^1-3, Jessica Tantivit^1-3, Mazen Nasrallah^1-4,7, Leyre Zubiri^2,4, Neal P. Smith^1-3, Alice Tirard^1-3, Swetha Ramesh^1-3, Benjamin Y. Arnold^1-3, Linda T. Nieman², Jon athan H. Chen^2-4,8, Thomas Eisenhaure³, Karin Pelka^2-4, Yuhui Song², Katherine H. Xu², Vjola Jorgji^2,8, Christopher J. Pinto^2,9, Tatyana Sharova⁹, Rachel Glasser⁵, PuiYee Chan^2,4, Ryan J. Sullivan^2,4, Hamed Khalili^3-5, Dejan Juric^2-4, Genevieve M. Boland^2,4,10, Michael Dougan^4-5, Nir Hacohen^2-4, Bo Li^1,3,11, Kerry L. Reynolds^2,4‡, and Alexandra-Chloé Villani^1-4,7‡†

Author affiliations

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

* These authors contributed equally: Molly Fisher Thomas, Kamil Slowikowski

‡These authors contributed equally: Kerry Reynolds, Alexnandra-Chloé Villani

† Correspondence to: mfthomas@partners.org; kslowikowski@mgh.harvard.edu; avillani@mgh.harvard.edu

bioRxiv 2021. doi: 10.1101/2021.09.17.460868

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, ITGAE^Hi CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs, and circulating ITGB2^Hi CD8 T cells recruited by ICAM and CXCR3 ligands. Cytotoxic GNLY^Hi CD4 T cells, ITGB2^Hi 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.

🔬 View the data

On this website, we provide interactive data browsers to view all of the transcriptomics data for each of the manually curated cell clusters.

Cell Clusters

Metadata variables and gene expression in two-dimensional embeddings.

Tissue immune cells:

CD8 T cells, CD4 T cells, Myeloid cells, B cells

Tissue epithelial and mesenchymal nuclei:

23 types of epithelial and mesenchymal nuclei

Blood immune cells:

CD8 T cells, CD4 T cells, Myeloid cells, B cells

View Cell Clusters

Gene Contrasts

Differential expression statistics for all genes:

3 contrasts
- irColitis Case vs Control
- Case PD1/CTLA4 vs Case PD1
- Control PD1 vs Control None
9 major cell lineages
105 cell clusters

View Gene Contrasts

📝 Cite our work

Here is the original preprint we posted to bioRxiv in 2021:

Thomas MF, Slowikowski K, Manakongtreecheep K, Sen P, Tantivit J, Nasrallah M, et al. Altered interactions between circulating and tissue-resident CD8 T cells with the colonic mucosa define colitis associated with immune checkpoint inhibitors. bioRxiv. 2021. p. 2021.09.17.460868. doi:10.1101/2021.09.17.460868

BibTex for bioRxiv preprint


  @UNPUBLISHED{Thomas2021,
    title    = "{Altered interactions between circulating and tissue-resident CD8
                T cells with the colonic mucosa define colitis associated with
                immune checkpoint inhibitors}",
    author   = "Thomas, Molly Fisher and Slowikowski, Kamil and
                Manakongtreecheep, Kasidet and Sen, Pritha and Tantivit, Jessica
                and Nasrallah, Mazen and Smith, Neal P and Ramesh, Swetha and
                Zubiri, Leyre and Tirard, Alice and Arnold, Benjamin Y and
                Nieman, Linda T and Chen, Jonathan H and Eisenhaure, Thomas and
                Pelka, Karin and Xu, Katherine H and Jorgji, Vjola and Pinto,
                Christopher J and Sharova, Tatyana and Glasser, Rachel and Chan,
                Elaina Puiyee and Sullivan, Ryan J and Khalili, Hamed and Juric,
                Dejan and Boland, Genevieve M and Dougan, Michael and Hacohen,
                Nir and Reynolds, Kerry L and Li, Bo and Villani,
                Alexandra-Chlo{\'e}",
    journal  = "bioRxiv",
    pages    = "2021.09.17.460868",
    month    =  sep,
    year     =  2021,
    language = "en",
    doi      = "10.1101/2021.09.17.460868"
  }

💾 Download the data

Analysis result files are available at Zenodo: 10.5281/zenodo.8088435

Single-cell expression data files are available at NCBI GEO: GSE206301

Sequencing reads are available at dbGAP: phs003418.v1.p1

💻 Read the source code

The code for our analysis and for this website is available at GitHub: github.com/villani-lab/ircolitis

✉ Contact us

Please contact us with any questions or comments.

The data presented here comes from the laboratory of Dr. Alexandra-Chloé Villani.