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

Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) which are more severe when ICIs are used in combination. A mouse model was developed to elucidate the molecular mechanisms of immune-related hepatitis, one of the common irAEs associated with ICIs. Molecular profiling by single cell RNA sequencing was 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 activated T cells. 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. Anti-CTLA4 antibody or isotype control was administered weekly to Pdcd1-/- mice. The IDO1 inhibitor, epacadostat, or vehicle control was administered by oral gavage twice daily. Anti-(4-1BB) agonistic antibody was administered intraperitoneally to mice twice weekly. Liver CD45+ cells were enriched with the Miltenyi liver dissociation kit and cells were analyzed on the 10X genomics platform.