IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.

Adult Aged Animals Cell Line Cell Line, Tumor Disease Progression Female Glioma / immunology HEK293 Cells Humans Immune Checkpoint Inhibitors / pharmacology Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism L-Amino Acid Oxidase / metabolism Leukemia, Lymphocytic, Chronic, B-Cell / immunology Male Mice Mice, Inbred C57BL Middle Aged Rats Receptors, Aryl Hydrocarbon / metabolism

AHR CLL IL4I1 T cell exhaustion adaptive immunity aryl hydrocarbon receptor interleukin 4 induced 1 kynurenic acid tryptophan metabolism tumor micro-environment

Journal

Cell

ISSN: 1097-4172

Titre abrégé: Cell

Pays: United States

ID NLM: 0413066

Informations de publication

Date de publication:
03 09 2020

Historique:

received: 16 12 2019

revised: 25 05 2020

accepted: 28 07 2020

pubmed: 21 8 2020

medline: 8 5 2021

entrez: 21 8 2020

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.cell.2020.07.038 PMID: 32818467

pubmed: 32818467

pii: S0092-8674(20)30946-6

doi: 10.1016/j.cell.2020.07.038

pii:

doi:

Substances chimiques

Immune Checkpoint Inhibitors 0

Indoleamine-Pyrrole 2,3,-Dioxygenase 0

Receptors, Aryl Hydrocarbon 0

IL4I1 protein, human EC 1.4.3.2

L-Amino Acid Oxidase EC 1.4.3.2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1252-1270.e34

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of Interests Three patent application families (PCT/US2020/025560, PCT/EP2020/060259, and EP19214890.6) have been filed on aspects of the described work. M. Seiffert. and C.A.O. receive and/or are planning to receive research funding from commercial organizations, like Bayer. C.A.O. is listed as inventor on PCT/EP2012/067504.