BibTex format
@article{Gudd:2024:10.1136/jitc-2023-008078,
author = {Gudd, C and Mitchell, E and Atkinson, S and Mawhin, M-A and Turajlic, S and Larkin, J and Thursz, M and Goldin, R and Powell, N and Antoniades, C and Woollard, K and Possamai, L and Triantafyllou, E},
doi = {10.1136/jitc-2023-008078},
journal = {Journal for ImmunoTherapy of Cancer},
title = {Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis},
url = {http://dx.doi.org/10.1136/jitc-2023-008078},
volume = {12},
year = {2024}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - Background 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 characterize the mechanism of CPI-hepatitis and to therapeutically target key pathways driving this pathology.Methods C57BL/6 wild-type (WT) mice were dosed with toll-like receptor (TLR)9 agonist (TLR9-L) for hepatic priming combined with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) plus anti-programmed cell death 1 (PD-1) (“CPI”) or phosphate buffered saline (PBS) control for up to 7 days. Flow cytometry, histology/immunofluorescence and messenger RNA sequencing were used to characterize liver myeloid/lymphoid subsets and inflammation. Hepatocyte damage was assessed by plasma alanine transaminase (ALT) and cytokeratin-18 (CK-18) measurements. In vivo investigations of CPI-hepatitis were carried out in Rag2−/− and Ccr2rfp/rfp transgenic mice, as well as following anti-CD4, anti-CD8 or cenicriviroc (CVC; CCR2/CCR5 antagonist) treatment.Results Co-administration of combination 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 ALT and CK-18 plasma levels. Liver RNA sequencing identified key signaling pathways (JAK-STAT, NF-ΚB) 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 on the presence of CCR2+ monocytes. The absence of hepatic monocyte recruitment in Ccr2rfp/rfp mice and CCR2 inhibition by CVC treatment in WT mice was able to prevent the development and reverse established experimental CPI-hepatitis.Conc
AU - Gudd,C
AU - Mitchell,E
AU - Atkinson,S
AU - Mawhin,M-A
AU - Turajlic,S
AU - Larkin,J
AU - Thursz,M
AU - Goldin,R
AU - Powell,N
AU - Antoniades,C
AU - Woollard,K
AU - Possamai,L
AU - Triantafyllou,E
DO - 10.1136/jitc-2023-008078
PY - 2024///
SN - 2051-1426
TI - Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis
T2 - Journal for ImmunoTherapy of Cancer
UR - http://dx.doi.org/10.1136/jitc-2023-008078
UR - https://jitc.bmj.com/content/12/4/e008078
VL - 12
ER -