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

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.

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles.

BACKGROUND: Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear. METHODS: Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab-sICB) or combination (nivolumab and ipilimumab-cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed. RESULTS: 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9-33.4) versus not-reached (P = 2.8 × 10-6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment. CONCLUSIONS: Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.

Peptide Receptor Radionuclide Treatment and (131)I-MIBG in the management of patients with metastatic/progressive phaeochromocytomas and paragangliomas.

BACKGROUND AND OBJECTIVES: Radionuclide therapy has been used to treat patients with progressive/metastatic paragangliomas (PGLs) and phaeochromocytomas (PCCs). The aim of the present study is to retrospectively compare the therapeutic outcomes of these modalities in patients with progressive/metastatic PCCs and PGLs. METHODS: Patients with progressive/metastatic PGLs and PCCs that were subjected to radionuclide treatment in our department were retrieved from our department's database for the period 1998-2013. Overall survival (OS), progression free survival (PFS), event free survival (EFS), and response to treatment were calculated. Treatment toxicity was documented. RESULTS: Twenty-two patients with progressive/metastatic PGLs or PCCs were treated with either (131)I-MIBG, (90)Y-DOTATATE or (177)Lu-DOTATATE. A total of 30 treatments were administered (16 treatments with (131)I-MIBG, 2 with (177)Lu-DOTATATE, and 12 with (90)Y-DOTATATE. Patients treated with PRRT had increased PFS and response to treatment compared to (131)I-MIBG treated patients (P < 0.05). However, difference in OS was non significant (P = 0.09). There was no difference in major toxicities between groups. When comparing only patients with PGLs, OS, PFS, EFS, and response to treatment were significantly higher in the PRRT treatment group. CONCLUSION: PRRT treatment offers increased OS, PFS, EFS, and response to treatment compared to (131)I-MIBG therapy in patients with progressive/malignant PGLs.

A guide to midgut neuroendocrine tumours (NETs) and carcinoid syndrome.

Patients with midgut neuroendocrine tumours or carcinoid syndrome often face a delayed diagnosis. This article aims to highlight the different ways in which patients with midgut neuroendocrine tumours (NETs) present, the diagnostic approach to them, the current methods of management available and future considerations.