IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.
Cell
; 182(5): 1252-1270.e34, 2020 09 03.
Article
en En
| MEDLINE
| ID: mdl-32818467
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Receptores de Hidrocarburo de Aril
/
L-Aminoácido Oxidasa
Límite:
Adult
/
Aged
/
Animals
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Cell
Año:
2020
Tipo del documento:
Article
País de afiliación:
Alemania