Activation and transcriptional profile of monocytes and CD8+ T cells are altered in checkpoint inhibitor-related hepatitis.
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. CD163, CCR2, CD68, CD3, CD8 and granzyme B expression was assessed using immunohistochemistry/immunofluorescence (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+/ CD68+CD163+ 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 CD163+/CCR2+ macrophage and CD8+ T cells.
|Authors:||Gudd CL, Au L, Triantafyllou E, Shum B, Liu T, Nathwani R, Kumar N, Mukherjee S, Dhar A, Woollard KJ, Yone Y, Pinato DJ, Thursz MR, Goldin RD, Gore ME, Larkin J, Khamri W, Antoniades CG, Turajlic S, Possamai LA,|
|Journal:||J Hepatol; 2021 Feb 22;S0168-8278(21)00108-2 doi:10.1016/j.jhep.2021.02.008|
|PubMed:||PMID: 33631227 (Go to PubMed)|