2. Academic Validation
  3. IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression

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

  • Cell. 2020 Sep 3;182(5):1252-1270.e34. doi: 10.1016/j.cell.2020.07.038.
Ahmed Sadik 1,  Luis F Somarribas Patterson 2,  Selcen Öztürk 3,  Soumya R Mohapatra 1,  Verena Panitz 4,  Philipp F Secker 5,  Pauline Pfänder 1,  Stefanie Loth 6,  Heba Salem 5,  Mirja Tamara Prentzell 5,  Bianca Berdel 5,  Murat Iskar 3,  Erik Faessler 7,  Friederike Reuter 5,  Isabelle Kirst 5,  Verena Kalter 3,  Kathrin I Foerster 8,  Evelyn Jäger 9,  Carina Ramallo Guevara 9,  Mansour Sobeh 10,  Thomas Hielscher 11,  Gernot Poschet 12,  Annekathrin Reinhardt 13,  Jessica C Hassel 14,  Marc Zapatka 3,  Udo Hahn 7,  Andreas von Deimling 13,  Carsten Hopf 9,  Rita Schlichting 15,  Beate I Escher 15,  Jürgen Burhenne 8,  Walter E Haefeli 8,  Naveed Ishaque 16,  Alexander Böhme 17,  Sascha Schäuble 18,  Kathrin Thedieck 19,  Saskia Trump 20,  Martina Seiffert 3,  Christiane A Opitz 21
Affiliations

Affiliations

  • 1 DKTK Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Faculty of Bioscience, Heidelberg University, 69120 Heidelberg, Germany.
  • 2 DKTK Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Faculty of Bioscience, Heidelberg University, 69120 Heidelberg, Germany; Department of Biochemistry, School of Medicine, University of Costa Rica (UCR), 11501-2060 San José, Costa Rica.
  • 3 Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 4 DKTK Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Neurology Clinic and National Center for Tumor Diseases, Heidelberg University Hospital, 69120 Heidelberg, Germany.
  • 5 DKTK Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 6 Department of Environmental Immunology, Helmholtz Centre for Environmental Research-UFZ, 04318 Leipzig, Germany; Institute of Organic Chemistry, Technical University Bergakademie Freiberg, 09596 Freiberg, Germany.
  • 7 Jena University Language & Information Engineering (JULIE) Lab, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
  • 8 Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
  • 9 Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), Mannheim University of Applied Sciences, 68163 Mannheim, Germany.
  • 10 Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, 69120 Heidelberg, Germany; AgroBioSciences Research Division, Mohammed VI Polytechnic University, 43150 Ben-Guerir, Morocco.
  • 11 Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 12 Centre for Organismal Studies (COS), University of Heidelberg, 69120 Heidelberg, Germany.
  • 13 Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, and Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 14 Department of Dermatology and National Center for Tumor Diseases, Heidelberg University Hospital, 69120 Heidelberg, Germany.
  • 15 Department of Cell Toxicology, Helmholtz Centre for Environmental Research-UFZ, 04318 Leipzig, Germany.
  • 16 Center for Digital Health, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), 10117 Berlin, Germany.
  • 17 Department of Ecological Chemistry, Helmholtz Centre for Environmental Research-UFZ, 04318 Leipzig, Germany.
  • 18 Jena University Language & Information Engineering (JULIE) Lab, Friedrich-Schiller-University Jena, 07743 Jena, Germany; Systems Biology and Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, 07745 Jena, Germany.
  • 19 Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, 6020 Innsbruck, Austria; Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands; Department of Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany.
  • 20 Molecular Epidemiology Unit, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), 10117 Berlin, Germany.
  • 21 DKTK Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Neurology Clinic and National Center for Tumor Diseases, Heidelberg University Hospital, 69120 Heidelberg, Germany. Electronic address: c.opitz@dkfz.de.
PMID: 32818467 DOI: 10.1016/j.cell.2020.07.038
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.

Keywords

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

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