Activation and transcriptional profile of monocytes and CD8+ T cells are altered in checkpoint inhibitor-related hepatitis.

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.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).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.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.

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Authors: Cathrin Lc Gudd, Lewis Au, Evangelos Triantafyllou, Benjamin Shum, Tong Liu, Rooshi Nathwani, Naveenta Kumar, Sujit Mukherjee, Ameet Dhar, Kevin J Woollard, You Yone, David J Pinato, Mark R Thursz, Robert D Goldin, Martin E Gore, James Larkin, Wafa Khamri, Charalambos G Antoniades, Samra Turajlic, Lucia A Possamai