Abstract
Background & AimsThe 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.MethodsWe 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.ResultsWe demonstrate CD8+ tissue resident memory T (TRM) 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+ TRM cell activation correlates with clinical and endoscopic ICI-colitis severity. Single-cell RNA sequencing analysis confirms activated CD8+ TRM 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.ConclusionsInterferon gamma–producing CD8+ TRM cells are a pathological hallmark of ICI-colitis and a novel target for therapy.
Highlights
BACKGROUND & AIMSThe pathogenesis of immune checkpoint inhibitor (ICI)–colitis remains incompletely understood
We sought to determine whether these CD8þ T cells had a tissue resident memory T cell (TRM) cell phenotype. We found that both ulcerative colitis (UC) and anti– CTLA-4/PD-1 dual checkpoint inhibitor colitis (DCC) groups are associated with increased proportions of CD3þ T cells in the affected tissue compared with healthy gut and anti–CTLA-4/PD-1 dual checkpoint inhibitor no colitis (DCNC)
The profound success of ICIs has resulted in broader applications, and an increasing incidence of ICI-colitis that is frequent and has the greatest overall immune-related adverse event (irAE) mortality.[3]
Summary
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. The pattern of gastrointestinal immunopathology is distinct from ulcerative colitis at both the immune and Gastroenterology Vol 161, No 4. ICI-colitis is a common adverse effect of checkpoint inhibitors, can mimic IBD, and currently has empirically derived treatment guidelines
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