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Gewebsresidente CD8+ T-Zellen als therapeutisches Ziel bei der Checkpunkttherapie-assoziierten Immunenterokolitis
Author(s) -
Bertram Bengsch
Publication year - 2022
Publication title -
karger kompass, autoimmun/karger kompass. autoimmun
Language(s) - English
Resource type - Journals
eISSN - 2624-8476
pISSN - 2624-8468
DOI - 10.1159/000522047
Subject(s) - colitis , ulcerative colitis , cd8 , immunology , immune system , medicine , t cell , flow cytometry , microbiology and biotechnology , biology , disease
Background & Aims: The pathogenesis of immune checkpoint inhibitor (ICI)-colitis remains incompletely understood. We sought to identify key cellular drivers of ICI-colitis and their similarities to idiopathic ulcerative colitis, and to determine potential novel therapeutic targets. Methods: We used a cross-sectional approach to study patients with ICI-colitis, those receiving ICI without the development of colitis, idiopathic ulcerative colitis, and healthy controls. A subset of patients with ICI-colitis were studied longitudinally. We applied a range of methods, including multiparameter and spectral flow cytometry, spectral immunofluorescence microscopy, targeted gene panels, and bulk and single-cell RNA sequencing. Results: We demonstrate CD8 + tissue resident memory T (T RM ) cells are the dominant activated T cell subset in ICI-colitis. The pattern of gastrointestinal immunopathology is distinct from ulcerative colitis at both the immune and epithelial-signaling levels. CD8 + T RM cell activation correlates with clinical and endoscopic ICI-colitis severity. Single-cell RNA sequencing analysis confirms activated CD8 + T RM cells express high levels of transcripts for checkpoint inhibitors and interferon-gamma in ICI-colitis. We demonstrate similar findings in both anti-CTLA-4/PD-1 combination therapy and in anti-PD-1 inhibitor-associated colitis. On the basis of our data, we successfully targeted this pathway in a patient with refractory ICI-colitis, using the JAK inhibitor tofacitinib. Conclusions: Interferon gamma-producing CD8 + T RM cells are a pathological hallmark of ICI-colitis and a novel target for therapy.

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