T cells and monocyte-derived myeloid cells mediate immunotherapy-related hepatitis in a mouse model

• Published in: Journal of hepatology 2021-11, Vol.75 (5), p.1083-1095
• Main Authors: Llewellyn, Heather P., Arat, Seda, Gao, Jingjin, Wen, Ji, Xia, Shuhua, Kalabat, Dalia, Oziolor, Elias, Virgen-Slane, Richard, Affolter, Timothy, Ji, Changhua
• Format: Article
• Language: English
• Subjects: 4-1BB; Animals; CD4 antigen; CD44 antigen; CD8 antigen; Cell activation; CTLA-4; CTLA-4 protein; Disease Models, Animal; Hepatitis; Hepatitis - immunology; Hepatocytes; IDO1; Immune checkpoint inhibitors; immune-related adverse events; Immunotherapy; Immunotherapy - methods; Immunotherapy - statistics & numerical data; Inflammation; ipilimumab; Liver; Liver injury; Lymphocytes; Lymphocytes T; Macrophages; Mice; Molecular modelling; Monocytes; Monocytes - immunology; Myeloid cells; Myeloid Cells - metabolism; nivolumab; PD-1; Phenotyping; T-Lymphocytes - immunology; Toxicity; Transcriptomics; γ-Interferon
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2021.06.037

Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) which are more severe when ICIs are used in combination. We aimed to use a mouse model to elucidate the molecular mechanisms of immune-related hepatitis, one of the common irAEs associated with ICIs. Immune phenotyping and molecular profiling were performed on Pdcd1-/- mice treated with anti-CTLA4 and/or the IDO1 inhibitor epacadostat or a 4-1BB agonistic antibody. ICI combination-induced hepatitis and 4-1BB agonist-mediated hepatitis share similar features yet maintain distinct immune signatures. Both were characterized by an expansion of periportal infiltrates and pan-zonal inflammation albeit with different morphologic characteristics. In both cases, infiltrates were predominantly CD4+ and CD8+ T cells with upregulated T-cell activation markers, ICOS and CD44. Depletion of CD8+ T cells abolished ICI-mediated hepatitis. Single-cell transcriptomics revealed that the hepatitis induced by combination ICIs is associated with a robust immune activation signature in all subtypes of T cells and T helper 1 skewing. Expression profiling revealed a central role for IFNγ and liver monocyte-derived macrophages in promoting a pro-inflammatory T-cell response to ICI combination and 4-1BB agonism. We developed a novel mouse model which offers significant value in yielding deeper mechanistic insight into immune-mediated liver toxicity associated with various immunotherapies. Hepatitis is one of the common immune-related adverse events in cancer patients receiving immune checkpoint inhibitor (ICI) therapy. The mechanisms of ICI-induced hepatitis are not well understood. In this paper, we identify key molecular mechanisms mediating immune intracellular crosstalk between liver T cells and macrophages in response to ICI in a mouse model. [Display omitted] •Pdcd1-/- mouse can be utilized as a model for immune checkpoint inhibitor-mediated liver injury.•Single-cell immune transcriptional profiling revealed a landscape of molecular pathways responding to inhibition of PD1, CTLA4 and IDO1.•We identified a subset-specific T cell activation signature and common IFNγ signature.•Monocyte-derived macrophages coordinate the T cell response to immune checkpoint inhibitors.