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Title

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

Authors
Gort-Freitas, Nicolas A
Messemaker, Marius
Gungabeesoon, Jeremy
Engblom, Camilla
Zilionis, Rapolas
Garris, Christopher
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Published in Science Immunology. 2021, vol. 6, no. 61, eabi7083
Abstract Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of TH1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-γ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-γ were not toxic themselves but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways after anti-PD-1 and anti-CTLA-4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in TH1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.
Identifiers
PMID: 34215680
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Research group Comprendre et manipuler le système immunitaire pour lutter contre le cancer (1024)
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(ISO format)
SIWICKI, Marie et al. Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy. In: Science Immunology, 2021, vol. 6, n° 61, p. eabi7083. doi: 10.1126/sciimmunol.abi7083 https://archive-ouverte.unige.ch/unige:152850

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Deposited on : 2021-07-08

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