A Metabolic Enzyme as a New Target for Cancer Immunotheraphy

This image depicts AHR as an important puzzle piece in tumor metabolism. IL4I1 and its tryptophan-derived metabolites act as key and key bit that activate AHR. The surrounding T cells represent the impact of IL4I1 on anti-tumor immunity. Image credit: Pauline Pfänder.

Scientists from e:Med junior alliance GlioPATH discovered that the metabolic enzyme IL4I1 promotes the spread of tumour cells and suppresses the immune system.  IL4I1 is produced to a greater extent in tumours and activates the dioxin receptor. Agents that inhibit IL4I1 could open up new opportunities for cancer therapy in the future. The scientists have now published their results in the journal Cell.

Immunotherapy activates the body’s own immune response against tumours and is currently revolutionising cancer therapy. However, despite individual groundbreaking successes, only a small number of patients benefit from the available drugs. The GlioPATH consortium has been investigating the molecular mechanisms that tumours use to escape destruction by the immune system. Their research results may provide important information for the development of new immunotherapy concepts.

The aryl hydrocarbon receptor (AHR) is also known as a dioxin receptor because it mediates the toxic effect of dioxins. However, not only toxins but also the body’s own metabolic products can activate the receptor. Tumours use the production of such metabolites to their advantage.

The breakdown products of the essential amino acid tryptophan, a building block for proteins that we take in with food, play an important role in the spread of tumours. However, the metabolic pathways that activate the dioxin receptor have not yet been sufficiently studied. To change this, the consortium systematically investigated which tryptophan-degrading enzymes are associated with dioxin receptor activation across 32 different tumour types. For their analysis, they combined information on gene activity in 32 tumour types with a computer-based language analysis. “Our algorithm searches the latest biomedical literature for genes regulated by the dioxin receptor,” explains bioinformatician Sascha Schäuble.

One molecule in particular caught the scientists’ eye: the enzyme IL4I1. No other enzyme of the tryptophan metabolism was as strongly linked to the activation of the dioxin receptor as IL4I1. “The metabolites formed by IL4I1 bind to the dioxin receptor and activate it, which leads to a suppression of immune cells,” explains chemist Saskia Trump. In patients* with gliomas, malignant brain tumours, it was shown that their probability of survival decreased when the enzyme IL4I1 was present in higher concentrations in these tumours. “The discovery of IL4I1 as a new target molecule for cancer therapy was only possible due to the interdisciplinary expertise that came together in our consortium,” stresses biochemist Kathrin Thedieck. “IL4I1 has great potential as a drug target. So far, substances that inhibit enzymes of the tryptophan metabolism have failed in clinical studies because the tumours did not respond to them. This could be because the role of IL4I1 has been ignored and it has therefore not yet been tested as a target molecule,” stresses Christiane Opitz, a physician and molecular cell biologist, looking at a possible clinical application of the study results.

Original publication:

IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression. Ahmed Sadik*, Luis F. Somarribas Patterson*, Selcen Öztürk*, Soumya R. Mohapatra*, Verena Panitz, Philipp F. Secker, Pauline Pfänder, Stefanie Loth, Heba Salem, Mirja Tamara Prentzell, Bianca Berdel, Murat Iskar, Erik Faessler, Friederike Reuter, Isabelle Kirst, Verena Kalter, Kathrin I. Foerster, Evelyn Jäger, Carina Ramallo Guevara, Mansour Sobeh, Thomas Hielscher, Gernot Poschet, Annekathrin Reinhardt, Jessica C. Hassel, Marc Zapatka,  Udo Hahn, Andreas von Deimling, Carsten Hopf, Rita Schlichting, Beate I. Escher, Jürgen Burhenne, Walter E. Haefeli, Naveed Ishaque, Alexander Böhme, Sascha Schäuble, Kathrin Thedieck, Saskia Trump#, Martina Seiffert#, Christiane A. Opitz#. Cell 2020

GlioPATH Consortium:

Dr. Christiane Opitz
Brain Cancer Metabolism
German Research Cancer Center, DKFZ, Heidelberg

Dr. Saskia Trump
Research Group Molecular Epidemiology
Charité - Universitätsmedizin Berlin and Berlin Institute of Health, BIH, Berlin
formerly Helmholtz Center for Environmental Research - UFZ, Leipzig

Prof. Dr. Kathrin Thedieck
Lab for Metabolic Signaling
Institut für Biochemie, University Innsbruck, Austria
Department für Neurowissenschaften, Universität Oldenburg, Deutschland
Department of Pediatrics, University of Groningen, University Medical Center Groningen, Niederlande

Dr. Sascha Schäuble
Systems Biology and Bioinformatics
Leibniz-Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institut (HKI), Jena
formerly Jena University Language & Information Engineering (JULIE) Lab, Friedrich-Schiller-Universität Jena, Jena

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