Interferon-Gamma–Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor–Colitis
Sarah C. Sasson, Stephanie Slevin, Vincent Cheung, Isar Nassiri, Anna Olsson‐Brown, Eve Fryer, Ricardo C. Ferreira, Dominik Trzupek, Tarun Gupta, Lulia Al‐Hillawi, Mari-lenna Issaias, Alistair Easton, Leticia Campo, Michael Fitzpatrick, Joss Adams, Meenali Chitnis, Andrew Protheroe, Mark Tuthill, Nicholas Coupe, Alison Simmons, Miranda Payne, Mark R. Middleton, Simon Travis, Benjamin P. Fairfax, Paul Klenerman, Oliver Brain
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: 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: cells are a pathological hallmark of ICI-colitis and a novel target for therapy.