Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

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Science Immunology  02 Jul 2021:
Vol. 6, Issue 61, eabi7083
DOI: 10.1126/sciimmunol.abi7083

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Distinction between toxicity and antitumor effects

Immune checkpoint blockade (ICB) has revolutionized cancer therapeutics; however, in many cases, ICB is limited by immune-related adverse events (irAEs). Thus, a better understanding of the immune responses that lead to irAEs and how they are distinguished from antitumor immunity is needed. Here, Siwicki et al. used anti-CD40 therapy as a mediator of TH1-induced antitumor immunity in mouse tumor models. They found that liver-resident Kupffer cells induced neutrophil-mediated liver toxicity by producing IL-12 and responding to IFN-γ. Inhibition of the neutrophil response limited liver toxicity while retaining the antitumor efficacy of anti-CD40. Similar data were found in patients treated with anti–PD-1 and anti–CTLA-4. Together, these data suggest that the toxicity of ICB can be inhibited without negatively affecting antitumor immunity.


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.

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