Siwicki, MarieMarieSiwickiGort-Freitas, Nicolas ANicolas AGort-FreitasMessemaker, MariusMariusMessemakerBill, RubenRubenBillGungabeesoon, JeremyJeremyGungabeesoonEngblom, CamillaCamillaEngblomZilionis, RapolasRapolasZilionisGarris, ChristopherChristopherGarrisGerhard, Genevieve MGenevieve MGerhardKohl, AnnaAnnaKohlLin, YunkangYunkangLinZou, Angela EAngela EZouCianciaruso, ChiaraChiaraCianciarusoBolli, EvangeliaEvangeliaBolliPfirschke, ChristinaChristinaPfirschkeLin, Yi-JangYi-JangLinPiot, CecileCecilePiotMindur, John EJohn EMindurTalele, NileshNileshTaleleKohler, Rainer HRainer HKohlerIwamoto, YoshikoYoshikoIwamotoMino-Kenudson, MariMariMino-KenudsonPai, Sara ISara IPaideVito, ClaudioClaudiodeVitoKoessler, ThibaudThibaudKoesslerMerkler, DoronDoronMerklerCoukos, AlexanderAlexanderCoukosWicky, AlexandreAlexandreWickyFraga, MontserratMontserratFragaSempoux, ChristineChristineSempouxJain, Rakesh KRakesh KJainDietrich, Pierre-YvesPierre-YvesDietrichMichielin, OlivierOlivierMichielinWeissleder, RalphRalphWeisslederKlein, Allon MAllon MKleinPittet, Mikael JMikael JPittet2024-10-112024-10-112021-07-02https://boris-portal.unibe.ch/handle/20.500.12422/87443Immunotherapy 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.en600 - Technology::610 - Medicine & healtharticle10.48350/1729233421568010.1126/sciimmunol.abi7083