Clinicopathological analysis of hepatic immune-related adverse events in comparison with autoimmune hepatitis and graft-versus host disease

Author:

Hagiwara Satoru,Watanabe Tomohiro,Kudo Masatoshi,Minaga Kosuke,Komeda Yoriaki,Kamata Ken,Kimura Masatomo,Hayashi Hidetoshi,Nakagawa Kazuhiko,Ueshima Kazuomi,Minami Yasunori,Aoki Tomoko,Takita Masahiro,Morita Masahiro,Cishina Hirokazu,Ida Hiroshi,Park Ah-Mee,Nishida Naoshi

Abstract

AbstractImmune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8+ T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs. Overall, the activation of CD8+ T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs.

Funder

Yakult BioScience Foundation

Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science

Smoking Research Foundation

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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