Deep Immune Phenotyping Reveals Distinct Immunopathogenesis in Checkpoint Inhibitor–Induced Colitis Compared with Ulcerative Colitis

Although initially assumed to be similar, immune checkpoint inhibitor (ICI)-induced autoimmunity can differ from spontaneous autoimmune disease in regard to clinical presentation, pathogenesis, and therapy. Despite limited pathogenetic understanding, ICI-induced colitis (irColitis), a common adverse event during ICI therapy, is treated analogously to its autoimmune counterpart, ulcerative colitis (UC). Thus, there is a tremendous need to characterize immunophenotypes in both forms of colonic inflammation to ultimately identify specific therapeutic strategies. In a multicenter study, local and systemic immunophenotypes of patients with irColitis were compared with those of patients with UC. Colonic mucosa, patient serum, and peripheral blood mononuclear cells (PBMC) of 20 patients with irColitis, 15 patients with UC, and 25 patients receiving ICI without toxicity were investigated. Immunophenotyping was performed using gene expression analyses of mucosal samples and PBMC, serum proteomics, and flow cytometry-based PBMC analysis. Mucosal gene expression analysis revealed higher expression of B cell- and TNF signaling-related genes in UC, whereas irColitis mucosa showed an upregulation of genes associated with effector T-cell responses and IFN signaling. Immunophenotyping of PBMC demonstrated increased activation and differentiation of T cells and higher expression of exhaustion markers in irColitis compared with UC. In contrast, dendritic cells and B cells demonstrated increased markers of activation in patients with UC. Taken together, irColitis is characterized by T cell-associated immunity, whereas B cell- and dendritic cell-mediated immune responses and TNF signaling are more important for UC immunopathogenesis. These observations could help identify more specific and efficient treatment strategies for irColitis.

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Journal
Cancer Immunology Research
Published
2025-04-18
DOI
https://doi.org/10.1158/2326-6066.cir-24-0387
Citations
1
Primary Topic
Cancer Immunotherapy and Biomarkers
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article
Field-Weighted Citation Impact
1.05
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article

Deep Immune Phenotyping Reveals Distinct Immunopathogenesis in Checkpoint Inhibitor–Induced Colitis Compared with Ulcerative Colitis

Thierry M. Nordmann, Ignazio Piseddu, Julia V. Mayerle, Michael Erdmann et al.
1 citations
Cancer Immunology Research
Cancer Immunotherapy and Biomarkers
1.05
article

Deep Immune Phenotyping Reveals Distinct Immunopathogenesis in Checkpoint Inhibitor–Induced Colitis Compared with Ulcerative Colitis

Thierry M. Nordmann, Ignazio Piseddu, Julia V. Mayerle, Michael Erdmann, Jimmy Retzlaff, David Anz, Giulia Pesch, Lars E. French, Stephan Ledderose, Thomas U. Schulz, Wolfgang Kruis, Rafaela Kramer, Michael Dougan, Maximilian Zwiebel, Claudia Kammerbauer, Frederick Klauschen, Nora Kramer, Julio Vera, Jörg Kumbrink, Georg Andreas Schett, Markus Eckstein, Matthias Mann, Lucie Heinzerling, Christina Schmitt, Jan Gaertig
article en
1 citations

Abstract

Although initially assumed to be similar, immune checkpoint inhibitor (ICI)-induced autoimmunity can differ from spontaneous autoimmune disease in regard to clinical presentation, pathogenesis, and therapy. Despite limited pathogenetic understanding, ICI-induced colitis (irColitis), a common adverse event during ICI therapy, is treated analogously to its autoimmune counterpart, ulcerative colitis (UC). Thus, there is a tremendous need to characterize immunophenotypes in both forms of colonic inflammation to ultimately identify specific therapeutic strategies. In a multicenter study, local and systemic immunophenotypes of patients with irColitis were compared with those of patients with UC. Colonic mucosa, patient serum, and peripheral blood mononuclear cells (PBMC) of 20 patients with irColitis, 15 patients with UC, and 25 patients receiving ICI without toxicity were investigated. Immunophenotyping was performed using gene expression analyses of mucosal samples and PBMC, serum proteomics, and flow cytometry-based PBMC analysis. Mucosal gene expression analysis revealed higher expression of B cell- and TNF signaling-related genes in UC, whereas irColitis mucosa showed an upregulation of genes associated with effector T-cell responses and IFN signaling. Immunophenotyping of PBMC demonstrated increased activation and differentiation of T cells and higher expression of exhaustion markers in irColitis compared with UC. In contrast, dendritic cells and B cells demonstrated increased markers of activation in patients with UC. Taken together, irColitis is characterized by T cell-associated immunity, whereas B cell- and dendritic cell-mediated immune responses and TNF signaling are more important for UC immunopathogenesis. These observations could help identify more specific and efficient treatment strategies for irColitis.

Cancer Immunology ResearchVol. 13(7)
Harvard University (US), University of Miami (US), University of Cologne (DE), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), LMU Klinikum (DE), Massachusetts General Hospital (US), Universitätsklinikum Erlangen (DE), Evangelisches Krankenhaus Kalk (DE), University Hospital of Zurich (CH), Dana-Farber Cancer Institute (US), Kliniken der Stadt Köln (DE), Comprehensive Cancer Center Erlangen (DE), Max Planck Institute of Biochemistry (DE), Krankenhaus Köln-Holweide (DE), Ludwig-Maximilians-Universität München (DE)
Good health and well-being
Openalex Percentile: Top 23%
Cancer Immunotherapy and Biomarkers
1.05
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