التفاصيل البيبلوغرافية
| العنوان: |
Interferon-Gamma–Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor–Colitis. |
| المؤلفون: |
Sasson, Sarah C., Slevin, Stephanie M., Cheung, Vincent T.F., Nassiri, Isar, Olsson-Brown, Anna, Fryer, Eve, Ferreira, Ricardo C., Trzupek, Dominik, Gupta, Tarun, Al-Hillawi, Lulia, Issaias, Mari-lenna, Easton, Alistair, Campo, Leticia, FitzPatrick, Michael E.B., Adams, Joss, Chitnis, Meenali, Protheroe, Andrew, Tuthill, Mark, Coupe, Nicholas, Simmons, Alison |
| المصدر: |
Gastroenterology (00165085); Oct2021, Vol. 161 Issue 4, p1229-1229, 1p |
| مستخلص: |
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. 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. 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. Interferon gamma–producing CD8+ T RM cells are a pathological hallmark of ICI-colitis and a novel target for therapy. [Display omitted] 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. [ABSTRACT FROM AUTHOR] |
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