IFNγ-producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis.

Abstract

BACKGROUND AND AIMS\nThe pathogenesis of immune checkpoint inhibitor (ICI)-colitis remains incompletely understood. We sought to identify key cellular driver(s) of ICI-colitis and their similarities to idiopathic ulcerative colitis (UC), and to determine potential novel therapeutic targets.\n\n\nMETHODS\nWe used a cross-sectional approach to study patients with ICI-colitis, those receiving ICI without the development of colitis, idiopathic UC and healthy controls. A subset of ICI-colitis patients were studied longitudinally. We applied a range of methods including multi-parameter and spectral flow cytometry, spectral immunofluorescence microscopy, targeted gene panels, bulk and single-cell RNASeq.\n\n\nRESULTS\nWe 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 UC at both the immune and epithelial-signalling level. CD8+ TRM cell activation correlates with clinical and endoscopic ICI-colitis severity. scRNASeq analysis confirms activated CD8+ TRM cells express high levels of transcripts for checkpoint inhibitors and IFNG 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.\n\n\nCONCLUSION\nIFNγ-producing CD8+ TRM cells are a pathological hallmark of ICI-colitis, and a novel target for therapy.