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

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Title: Activation and transcriptional profile of monocytes and CD8+ T cells are altered in checkpoint inhibitor-related hepatitis
Authors: Possamai, L
Gudd, C
Au, L
Triantafyllou, E
Shum, B
Liu, T
Nathwani, R
Kumar, N
Mukherjee, S
Dhar, A
Woollard, K
Yone, Y
Pinato, D
Thursz, M
Goldin, R
Gore, M
Larkin, J
Khamri, W
Antoniades, C
Turajlic, S
Item Type: Journal Article
Abstract: Background & Aims: 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. 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 (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). Results: 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. Conclusions: 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. Lay summary: 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.
Issue Date: Jul-2021
Date of Acceptance: 9-Feb-2021
URI: http://hdl.handle.net/10044/1/87846
DOI: 10.1016/j.jhep.2021.02.008
ISSN: 0168-8278
Publisher: Elsevier
Start Page: 177
End Page: 189
Journal / Book Title: Journal of Hepatology
Volume: 75
Issue: 1
Copyright Statement: © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: Academy of Medical Sciences
Keywords: immune checkpoint
immunotherapy-related hepatitis
1103 Clinical Sciences
1117 Public Health and Health Services
Gastroenterology & Hepatology
Publication Status: Published
Online Publication Date: 2021-02-22
Appears in Collections:Department of Immunology and Inflammation
Department of Metabolism, Digestion and Reproduction
Department of Surgery and Cancer
Faculty of Medicine

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