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

Autor: Christiane A. Opitz, Alexander Böhme, Saskia Trump, Erik Faessler, Mirja Tamara Prentzell, Friederike Reuter, Andreas von Deimling, Walter E. Haefeli, Bianca Berdel, Evelyn Jäger, Carina Ramallo Guevara, Verena Kalter, Marc Zapatka, Jessica C. Hassel, Sascha Schäuble, Gernot Poschet, Annekathrin Reinhardt, Jürgen Burhenne, Mansour Sobeh, Naveed Ishaque, Carsten Hopf, Martina Seiffert, Philipp F Secker, Rita Schlichting, Stefanie Loth, Beate I. Escher, Luis F. Somarribas Patterson, Selcen Öztürk, Udo Hahn, Soumya R. Mohapatra, Kathrin Thedieck, Pauline Pfänder, Isabelle Kirst, Ahmed Sadik, Murat Iskar, Thomas Hielscher, Verena Panitz, Kathrin I. Foerster, Heba Salem
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Adult
Male
Chronic lymphocytic leukemia
animal diseases
chemical and pharmacologic phenomena
Biology
L-Amino Acid Oxidase
General Biochemistry
Genetics and Molecular Biology
Cell Line
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Kynurenic acid
Immunity
Cell Line
Tumor
medicine
Animals
Humans
Indoleamine-Pyrrole 2
3
-Dioxygenase
Immune Checkpoint Inhibitors
030304 developmental biology
Aged
0303 health sciences
Glioma
Middle Aged
biochemical phenomena
metabolism
and nutrition
Aryl hydrocarbon receptor
medicine.disease
Acquired immune system
Leukemia
Lymphocytic
Chronic
B-Cell
Immune checkpoint
3. Good health
Rats
Mice
Inbred C57BL
HEK293 Cells
chemistry
Receptors
Aryl Hydrocarbon
Tumor progression
Cancer cell
biology.protein
Cancer research
Disease Progression
bacteria
Female
030217 neurology & neurosurgery
Zdroj: Cell
Cell, 182(5), 1252-1270.e34. CELL PRESS
ISSN: 0092-8674
Popis: 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.
Databáze: OpenAIRE
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