Siwicki, Marie; Gort-Freitas, Nicolas A; Messemaker, Marius; Bill, Ruben; Gungabeesoon, Jeremy; Engblom, Camilla; Zilionis, Rapolas; Garris, Christopher; Gerhard, Genevieve M; Kohl, Anna; Lin, Yunkang; Zou, Angela E; Cianciaruso, Chiara; Bolli, Evangelia; Pfirschke, Christina; Lin, Yi-Jang; Piot, Cecile; Mindur, John E; Talele, Nilesh; Kohler, Rainer H; ... (2021). Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy. Science immunology, 6(61) American Association for the Advancement of Science 10.1126/sciimmunol.abi7083
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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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology |
UniBE Contributor: |
Bill, Ruben |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2470-9468 |
Publisher: |
American Association for the Advancement of Science |
Language: |
English |
Submitter: |
Rebeka Gerber |
Date Deposited: |
16 Sep 2022 10:27 |
Last Modified: |
05 Dec 2022 16:24 |
Publisher DOI: |
10.1126/sciimmunol.abi7083 |
PubMed ID: |
34215680 |
BORIS DOI: |
10.48350/172923 |
URI: |
https://boris.unibe.ch/id/eprint/172923 |
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