Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy.

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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