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Cell Rep. 2014 Jun 26;7(6):1914-25. doi: 10.1016/j.celrep.2014.05.006. Epub 2014 May 29.

IKKα promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells.

Author information

1
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.
2
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.
3
Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
4
Department of Radiology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
5
Institute of Pathology, Ludwig-Maximilian-University, 80337 Munich, Germany.
6
Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, 91054 Erlangen, Germany.
7
Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21701, USA.
9
Department of Clinical Chemistry, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
10
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.
11
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.
12
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
13
Unit of Signal Transduction (GIGA-ST), GIGA-R, University of Liege and WELBIO, CHU, Sart-Tilman, 4000 Liege, Belgium.
14
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.

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.

PMID:
24882009
DOI:
10.1016/j.celrep.2014.05.006
[Indexed for MEDLINE]
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