Understanding the pathogenesis of immune checkpoint inhibitor-induced hepatitis

Cathrin Luisa Carolin Gudd, Lucia Possamai, Wafa Khamri, Kevin Woollard, Robert Goldin, The Royal Marsden Cancer Charity
Checkpoint inhibitors (CPIs) targeting cytotoxic T lymphocyte antigen- 4 (CTLA-4) and programmed cell death-1 (PD-1) are a novel class of cancer treatments, which stimulate anti-tumour immune responses. CPI treatment is frequently complicated by immune-related adverse events (irAE), including CPI- induced hepatitis (CPI-Hep), which represents one of the most common toxicities. This is a critical burden to treating malignancies, as CPI-related organ toxicities often require discontinuity of
more » ... ment and high-dose immunosuppression. This research aims to give insights into the underlying immunopathology of CPI-Hep and to highlight potential therapeutic pathways using both human samples and experimental models. Methods: Flow cytometry and gene expression assays were used for in-depth characterisation of phenotype, functionality and transcriptional immune-profile of peripheral monocyte and T cells in patients with CPI-Hep. Intra-hepatic immune cells were assessed by immunohistochemistry. Using C57BL/6 wild-type mice, stimuli of hepatic inflammation [e.g. toll-like receptor ligands (TLR-L)] in combination with CPI treatment were trialled for the induction of experimental CPI-Hep. In vivo mechanistic investigations of CPI-Hep were carried out in Rag2-/- and Ccr2rfp/rfp transgenic mice. Results: Human CPI-Hep is associated with an activated, tissue homing phenotype of peripheral CCR2highCCR7lowCD163high monocytes and HLA-DRhighICOShighTim- 3highCD8+ effector T cells with enhanced cytotoxicity. Liver biopsies mirrored the peripheral phenotype and revealed inflammatory clusters of CCR2+ macrophages with cytotoxic CD8+ T cells. In mice, co-administration of TLR9-L with CPIs mimicked human disease with mixed cytotoxic CD8+/CCR2+ monocyte/macrophage inflammatory aggregates and hepatocellular injury. In vivo investigation further revealed that CCR2+ monocytes are required for CD8+ T cell liver recruitment, while cytotoxic CD8+ T cells may play a role in mediating hepatocellular injury. Conclusions: This work prov [...]
doi:10.25560/85786 fatcat:ratzttv2qbfnfgjg2yzc5anoqq