RESUMO
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.
Assuntos
Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/efeitos adversos , Células de Kupffer/efeitos dos fármacos , Fígado/efeitos dos fármacos , Neoplasias/terapia , Neutrófilos/efeitos dos fármacos , Animais , Antígenos CD40/antagonistas & inibidores , Antígenos CD40/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Citocinas/imunologia , Humanos , Células de Kupffer/imunologia , Fígado/imunologia , Camundongos Transgênicos , Neoplasias/imunologia , Neutrófilos/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologiaRESUMO
Tumor cells utilize glucose to engage in aerobic glycolysis, fulfilling their metabolic demands for extensive proliferation. A recent study in Nature discovers that tumor-infiltrating myeloid cells exhibit a superior glucose uptake capacity over tumor cells, which present enhanced glutamine metabolism, suggesting that nutrient partitioning in the TME might be more complex than previously thought.
Assuntos
Glicólise , Neoplasias , Proliferação de Células , Ciclo do Ácido Cítrico , Glucose , Glutamina/metabolismo , HumanosRESUMO
Myeloid cells co-expressing the markers CD11b, Ly-6G, and SiglecF can be found in large numbers in murine lung adenocarcinomas and accelerate cancer growth by fostering tumor cell invasion, angiogenesis, and immunosuppression; however, some of these cells' fundamental features remain unexplored. Here, we show that tumor-infiltrating CD11b+ Ly-6G+ SiglecFhigh cells are bona fide mature neutrophils and therefore differ from other myeloid cells, including SiglecFhigh eosinophils, SiglecFhigh macrophages, and CD11b+ Ly-6G+ myeloid-derived suppressor cells. We further show that SiglecFhigh neutrophils gradually accumulate in growing tumors, where they can live for several days; this lifespan is in marked contrast to that of their SiglecFlow counterparts and neutrophils in general, which live for several hours only. Together, these findings reveal distinct attributes for tumor-promoting SiglecFhigh neutrophils and help explain their deleterious accumulation in the tumor bed.