Interferon-Gamma-Producing CD8 + Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor-Colitis

Gastroenterology. 2021 Oct;161(4):1229-1244.e9. doi: 10.1053/j.gastro.2021.06.025. Epub 2021 Jun 17.

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.

Keywords: Checkpoint Colitis; Immunotherapy Colitis; Tofacitinib; Ulcerative Colitis.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / metabolism
  • Case-Control Studies
  • Colitis / chemically induced*
  • Colitis / drug therapy
  • Colitis / immunology
  • Colitis / metabolism
  • Colitis, Ulcerative / immunology
  • Colitis, Ulcerative / metabolism
  • Colon / drug effects*
  • Colon / immunology
  • Colon / metabolism
  • Cross-Sectional Studies
  • Gene Expression Profiling
  • Humans
  • Immune Checkpoint Inhibitors / adverse effects*
  • Immunologic Memory / drug effects*
  • Interferon-gamma / metabolism*
  • Longitudinal Studies
  • Lymphocyte Activation / drug effects
  • Memory T Cells / drug effects*
  • Memory T Cells / immunology
  • Memory T Cells / metabolism
  • Phenotype
  • Piperidines / therapeutic use
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / metabolism
  • Prospective Studies
  • Pyrimidines / therapeutic use
  • RNA-Seq
  • Single-Cell Analysis
  • Transcriptome

Substances

  • CTLA-4 Antigen
  • CTLA4 protein, human
  • IFNG protein, human
  • Immune Checkpoint Inhibitors
  • PDCD1 protein, human
  • Piperidines
  • Programmed Cell Death 1 Receptor
  • Pyrimidines
  • Interferon-gamma
  • tofacitinib