Research ArticleCANCER IMMUNOLOGY

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.

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