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

J Hepatol. 2021 Jul;75(1):177-189. doi: 10.1016/j.jhep.2021.02.008. Epub 2021 Feb 22.

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.

Keywords: immune checkpoint; immunotherapy; immunotherapy-related hepatitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / immunology*
  • Antigens, Differentiation, Myelomonocytic / immunology*
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • CD8-Positive T-Lymphocytes / immunology*
  • Chemical and Drug Induced Liver Injury* / blood
  • Chemical and Drug Induced Liver Injury* / etiology
  • Chemical and Drug Induced Liver Injury* / immunology
  • Chemical and Drug Induced Liver Injury* / prevention & control
  • Drug Discovery
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / administration & dosage
  • Immune Checkpoint Inhibitors / adverse effects*
  • Immune Checkpoint Inhibitors / immunology
  • Macrophage Activation / immunology
  • Macrophages / immunology*
  • Male
  • Middle Aged
  • Receptors, CCR2 / immunology*
  • Receptors, CCR7 / immunology*
  • Receptors, Cell Surface / immunology*
  • T-Lymphocytes, Cytotoxic / immunology

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Antineoplastic Agents
  • CCR2 protein, human
  • CCR7 protein, human
  • CD163 antigen
  • Immune Checkpoint Inhibitors
  • Receptors, CCR2
  • Receptors, CCR7
  • Receptors, Cell Surface