title: IKKα promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells.
abstract: The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ)-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC) therapy.
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Unit of Signal Transduction (GIGA-ST), GIGA-R, University of Liege and WELBIO, CHU, Sart-Tilman, 4000 Liege, Belgium.
authors.forename: Serkan I
authors.initials: SI
authors.lastname: Göktuna
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany.
authors.forename: Ozge
authors.initials: O
authors.lastname: Canli
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bollrath
authors.affiliation: Department of Radiology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Fingerle
authors.affiliation: Institute of Pathology, Ludwig-Maximilian-University, 80337 Munich, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Horst
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany.
authors.forename: Michaela A
authors.initials: MA
authors.lastname: Diamanti
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany.
authors.forename: Charles
authors.initials: C
authors.lastname: Pallangyo
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Bennecke
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Nebelsiek
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Mankan
authors.affiliation: Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.affiliation: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: David
authors.initials: D
authors.lastname: Artis
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21701, USA.
authors.forename: Yinling
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Clinical Chemistry, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Patzelt
authors.affiliation: Department of Clinical Chemistry, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: Institute of Pathology, Ludwig-Maximilian-University, 80337 Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: M Mark
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Unit of Signal Transduction (GIGA-ST), GIGA-R, University of Liege and WELBIO, CHU, Sart-Tilman, 4000 Liege, Belgium.
authors.forename: Alain
authors.initials: A
authors.lastname: Chariot
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Melek C
authors.initials: MC
authors.lastname: Arkan
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: greten@gsh.uni-frankfurt.de.
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000473:pathology; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D016764:Cell Polarity; D002471:Cell Transformation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007422:Intestines / Q000276:immunology*; D007694:Killer Cells, Natural / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology* / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D051550:I-kappa B Kinase