IKKα Promotes Intestinal Tumorigenesis by Limiting Recruitment of M1-like Polarized Myeloid Cells
Serkan I. Göktuna,
Ozge Canli,
Julia Bollrath,
Alexander A. Fingerle,
David Horst,
Michaela A. Diamanti,
Charles Pallangyo,
Moritz Bennecke,
Tim Nebelsiek,
Arun K. Mankan,
Roland Lang,
David Artis,
Yinling Hu,
Thomas Patzelt,
Jürgen Ruland,
Thomas Kirchner,
M. Mark Taketo,
Alain Chariot,
Melek C. Arkan,
Florian R. Greten
Affiliations
Serkan I. Göktuna
Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
Ozge Canli
Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
Julia Bollrath
Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
Alexander A. Fingerle
Department of Radiology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
David Horst
Institute of Pathology, Ludwig-Maximilian-University, 80337 Munich, Germany
Michaela A. Diamanti
Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
Charles Pallangyo
Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
Moritz Bennecke
Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
Tim Nebelsiek
Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
Arun K. Mankan
Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
Roland Lang
Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, 91054 Erlangen, Germany
David Artis
Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Yinling Hu
Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21701, USA
Thomas Patzelt
Department of Clinical Chemistry, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
Jürgen Ruland
Department of Clinical Chemistry, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
Thomas Kirchner
Institute of Pathology, Ludwig-Maximilian-University, 80337 Munich, Germany
M. Mark Taketo
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
Alain Chariot
Unit of Signal Transduction (GIGA-ST), GIGA-R, University of Liege and WELBIO, CHU, Sart-Tilman, 4000 Liege, Belgium
Melek C. Arkan
Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
Florian R. Greten
Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
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.
