RESUMO
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.
Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Colite/induzido quimicamente , Colo/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/efeitos adversos , Memória Imunológica/efeitos dos fármacos , Interferon gama/metabolismo , Células T de Memória/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Estudos de Casos e Controles , Colite/tratamento farmacológico , Colite/imunologia , Colite/metabolismo , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Colo/imunologia , Colo/metabolismo , Estudos Transversais , Perfilação da Expressão Gênica , Humanos , Estudos Longitudinais , Ativação Linfocitária/efeitos dos fármacos , Células T de Memória/imunologia , Células T de Memória/metabolismo , Fenótipo , Piperidinas/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Estudos Prospectivos , Pirimidinas/uso terapêutico , RNA-Seq , Análise de Célula Única , TranscriptomaRESUMO
A man in his 80s was undergoing immunotherapy with pembrolizumab, an anti-PD-1 monoclonal antibody, following his diagnosis of adenocarcinoma of primary lung origin. 24 weeks into treatment, the patient reported experiencing loose stools associated with malaise and poor appetite but no further symptoms. This progressed in frequency and a clinical diagnosis of grade 2 immune checkpoint inhibitor colitis was made. Management with oral prednisolone was commenced but symptoms persisted. Common enteric infections had been ruled out, as were coeliac disease and hyperthyroidism. Flexible sigmoidoscopy and colonoscopy results were not in keeping with colitis, having revealed normal looking mucosa. Following this, a faecal elastase level was found to be low. A diagnosis of pembrolizumab-induced pancreatic exocrine insufficiency was made, and stool frequency and consistency swiftly improved following the use of pancreatic enzyme replacement therapy.