Altered activation and transcriptional profile in monocytes and CD8+ T cells in checkpoint inhibitor-related hepatitis
Abstract Background & Aims: Checkpoint inhibitor-related hepatitis (CPI-Hep) is an emerging clinical challenge. We aim to gain insights into the immunopathology of CPI-Hep by comprehensive characterisation of myeloid and lymphoid subsets. Methods: CPI-treated patients with or without related hepatitis (CPI-Hep; n=22 and CPI-noHep; n=7) were recruited. Phenotypic and transcriptional-profiling of peripheral immune subsets was performed and compared with 19 healthy controls (HC). In vitro monocyte-derived macrophages (MoMF) were assessed for activation and cytokine production. CCR2, CD68, CD3, CD8 and granzyme B expression was assessed using immunohistochemistry (n=4). Results: A significant total monocyte depletion was observed in CPI-Hep compared with HC (p=0.04), along with a proportionate increase in the classical monocyte population (p=0.0002) and significant upregulation of CCR2, CD163 and downregulation of CCR7. Soluble CD163 levels were significantly elevated in CPI-Hep compared with HC (p<0.0001). In vitro MoMF from CPI-Hep showed enhanced production of pro-inflammatory cytokines. CD8+ T cells demonstrated increased perforin, granzyme B, ICOS and HLA-DR expression in CPI-Hep. Transcriptional profiling supported activated monocyte and enhanced effector CD8+ T cell populations in CPI-Hep. Immunohistochemistry demonstrated co-localisation of CD8+/granzyme B+ T cells with CD68+/CCR2+ macrophages in CPI-Hep liver tissue. Conclusions: CPI-Hep is associated with an activation of peripheral monocytes and enhanced cytotoxic, effector phenotype of CD8+ T cells. These changes were reflected by liver inflammation composed of CCR2+ macrophage and CD8+ T cells.