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- W4385953430 abstract "Abstract Checkpoint inhibitor-induced hepatitis (CPI-hepatitis) is an emerging problem with the widening use of CPIs in cancer immunotherapy. Here, we developed a mouse model to characterise the mechanism of CPI-hepatitis and to therapeutically target key pathways driving this pathology. C57BL/6 wild-type (WT) mice were dosed with TLR9-agonist (TLR9-L) for hepatic priming combined with anti-CTLA-4 plus anti-PD-1 (CPI) or control (PBS) for up to 7 days. Co-administration of CPIs with TLR9-L induced liver pathology closely resembling human disease, with increased infiltration and clustering of granzyme B + perforin + CD8 + T cells and CCR2 + monocytes, 7 days post treatment. This was accompanied by apoptotic hepatocytes surrounding these clusters and elevated cytokeratin-18 and alanine transaminase plasma levels. Liver RNA sequencing identified key signalling pathways (JAK-STAT, NF- κ B) and cytokine/chemokine networks ( Ifnγ, Cxcl9, Ccl2/Ccr2 ) as drivers of CPI-hepatitis. Using this model, we show that CD8 + T cells mediate hepatocyte damage in experimental CPI-hepatitis. However, their liver recruitment, clustering, and cytotoxic activity is dependent the presence of CCR2 + monocytes. Absence of hepatic monocyte recruitment in Ccr2 rfp/rfp mice and CCR2 therapeutic inhibition by cenicriciroc (CVC) in WT mice prevented CPI-hepatitis. In conclusion, using this newly established mouse model, we demonstrate a central role of liver infiltrating CCR2 + monocyte interaction with cytotoxic CD8 + T cells in the pathogenesis of CPI-hepatitis and highlight novel therapeutic targets." @default.
- W4385953430 created "2023-08-18" @default.
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- W4385953430 date "2023-08-16" @default.
- W4385953430 modified "2023-10-05" @default.
- W4385953430 title "Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis" @default.
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- W4385953430 doi "https://doi.org/10.1101/2023.08.14.553197" @default.
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