RESUMO
Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.
Assuntos
L-Aminoácido Oxidase/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Adulto , Idoso , Animais , Linhagem Celular , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Glioma/imunologia , Glioma/metabolismo , Glioma/terapia , Células HEK293 , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , RatosRESUMO
The effective treatment of cerebral metastases from HER2-positive breast cancer remains an unmet need. Recent studies indicate that activated astrocytes and brain endothelial cells exert chemoprotective effects on cancer cells through direct physical interaction. Here we report that the endothelin axis mediates protection of HER2-amplified brain metastatic breast cancers to the anti-HER2 antibody-drug conjugate ado-trastuzumab emtansine (T-DM1). Macitentan, a dual inhibitor of endothelin receptors A and B, improves the efficacy of T-DM1 against breast cancers grown in the brain. We show that direct contact of brain stroma with cancer cells is required for protection to T-DM1. Our data suggest that targeting the endothelin axis may be beneficial when anti-signaling agent and cytotoxic agent are combined. These findings may contribute to the development of therapeutic approaches with enhanced efficacy in the brain microenvironment.