Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of hepatology, 2021-07, Vol.75 (1), p.177-189

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Checkpoint inhibitor-related hepatitis (CPI-Hep) is an emerging clinical challenge. We aimed to gain insights into the immunopathology of CPI-Hep by comprehensively characterising 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 (HCs). In vitro monocyte-derived macrophages (MoMFs) 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 HCs (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 HCs (p <0.0001). In vitro MoMFs 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 indicated the presence of 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 activation of peripheral monocytes and an enhanced cytotoxic, effector CD8+ T cell phenotype. These changes were reflected by liver inflammation composed of CD163+/CCR2+ macrophages and CD8+ T cells. Some patients who receive immunotherapy for cancer develop liver inflammation, which requires cessation of cancer treatment. Herein, we describe ways in which the white blood cells of patients who develop liver inflammation differ from those of patients who receive the same immunotherapy but do not experience liver-related side effects. Targeting some of the pathways we identify may help to prevent or manage this side effect and facilitate cancer treatment. [Display omitted] •CPI-Hepatitis is associated with peripheral monocyte activation (CD163hi, CCR2hi).•Peripheral CD8 T cells in CPI-Hepatitis showed elevated activation/cytotoxicity.•Liver immunohistochemistry showed CD8 T cell/macrophage aggregates in CPI-Hepatitis.•Monocyte-derived macrophages from CPI-Hepatitis show enhanced cytokine secretion in vitro.