1. Immune Checkpoint Inhibitor Colitis: Resident Memory Unleashed
- Author
-
Michael Dougan
- Subjects
Immunotherapy Colitis ,ICI, immune checkpoint inhibitor ,Immune checkpoint inhibitors ,HV, healthy volunteer ,PD-1, programmed cell death protein 1 ,cDNA, complementary DNA ,Full Report: Basic and Translational—Alimentary Tract ,Text mining ,medicine ,Humans ,Ulcerative Colitis ,IFNG, interferon gamma ,Colitis ,Immune Checkpoint Inhibitors ,Original Research ,DCC, anti–CTLA-4/PD-1 dual checkpoint inhibitor colitis ,Hepatology ,FMT, fecal microbiota transplantation ,business.industry ,UCEIS, Ulcerative Colitis Endoscopic Index of Severity ,scRNA, single-cell RNA ,Gastroenterology ,TRM, tissue resident memory T cell ,medicine.disease ,RNASeq, RNA sequencing ,PDC, anti–PD-1-monotherapy colitis ,UC, ulcerative colitis ,Tofacitinib ,Immunology ,Checkpoint Colitis ,DCNC, anti–CTLA-4/PD-1 dual checkpoint inhibitor no colitis ,business ,irAE, immune-related adverse event - Abstract
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 (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. Conclusions Interferon gamma–producing CD8+ TRM cells are a pathological hallmark of ICI-colitis and a novel target for therapy., Graphical abstract, We present an analysis of the immunopathology in checkpoint-inhibitor colitis, a common adverse effect of cancer immunotherapy. We used our findings to successfully identify a novel therapy for a case of refractory colitis.
- Published
- 2021