RESUMO
Macrophages often abound within tumors, express colony-stimulating factor 1 receptor (CSF1R), and are linked to adverse patient survival. Drugs blocking CSF1R signaling have been used to suppress tumor-promoting macrophage responses; however, their mechanisms of action remain incompletely understood. Here, we assessed the lung tumor immune microenvironment in mice treated with BLZ945, a prototypical small-molecule CSF1R inhibitor, using single-cell RNA sequencing and mechanistic validation approaches. We showed that tumor control was not caused by CSF1R+ cell depletion; instead, CSF1R targeting reshaped the CSF1R+ cell landscape, which unlocked cross-talk between antitumoral CSF1R- cells. These cells included IFNγ-producing natural killer and T cells, and an IL12-producing dendritic cell subset, denoted as DC3, which were all necessary for CSF1R inhibitor-mediated lung tumor control. These data indicate that CSF1R targeting can activate a cardinal cross-talk between cells that are not macrophages and that are essential to mediate the effects of T cell-targeted immunotherapies and promote antitumor immunity.See related Spotlight by Burrello and de Visser, p. 4.
Assuntos
Células Dendríticas/imunologia , Imunoterapia/métodos , Interferon gama/metabolismo , Interleucina-12/metabolismo , Neoplasias Pulmonares/terapia , Animais , Benzotiazóis/farmacologia , Linhagem Celular Tumoral , Feminino , Neoplasias Pulmonares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Picolínicos/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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
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.