Gaining deeper mechanistic insights into immunotherapy-mediated liver toxicity

Llewellyn H, Arat S, Gao J, et al. T cells and monocyte-derived myeloid cells mediate immunotherapy-related hepatitis in a mouse model. J Hepatol 2021; S0168-8278(21)01887-0. doi: 10.1016/j.jhep.2021.06.037.

Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated protein 4, programmed cell death 1 or indoleamine 2,3-dioxygenase 1 have demonstrated antitumour efficacy in several types of cancers. Normally, these inhibitory pathways, or checkpoints, maintain the balance between T-cell activation and inhibition. Disruption of these checkpoints results in enhanced antitumour immune response but can cause undesirable off-target immune-mediated inflammatory events such as hepatitis. ICI-associated hepatitis has morphologic characteristics that are generally reminiscent of autoimmune disease. However, the exact mechanisms of these events have not been elucidated and there are no animal models exhibiting ICI-induced hepatitis. In a recently developed PD1−/− mouse model, ICI combination-induced hepatitis and the 4-1BB (tumour necrosis factor ligand superfamily member 9) agonist-mediated hepatitis shared similar features, yet maintained distinct immune signatures. Both were characterised by an expansion of periportal infiltrates and pan-zonal inflammation although with different morphologic characteristics. In both cases, infiltrates were predominantly cluster of differentiation 4 (CD4+) and CD8+ T cells with upregulated T-cell activation markers inducible T-cell costimulator and CD44 (homing cell adhesion molecule). Depletion of CD8+ T cells abolished the ICI-mediated hepatitis. Single-cell transcriptomics revealed that the hepatitis induced by combination of ICIs is associated with a robust immune activation signature in all subtypes of T cells and helper T cell 1 (Th1) skewing. Expression profiling revealed a central role for interferon gamma and liver monocyte-derived macrophages in promoting a proinflammatory T-cell response to ICI combination and 4-1BB agonism. This mouse model is of important value for the investigation of the immune mechanisms, disease pathogenesis and therapy in the evaluation of liver toxicities of new ICI inhibitors. However, its limitation is that it represents a less severe …