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T cells and monocyte-derived myeloid cells mediate immunotherapy-related hepatitis in a mouse model.
- Source :
-
Journal of Hepatology . Nov2021, Vol. 75 Issue 5, p1083-1095. 13p. - Publication Year :
- 2021
-
Abstract
- 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] • P dcd 1 -/- 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01688278
- Volume :
- 75
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Journal of Hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 152847153
- Full Text :
- https://doi.org/10.1016/j.jhep.2021.06.037