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J. Exp. Med. 205 (6): 1261-1268

Copyright © 2008 by the Rockefeller University Press.

BRIEF DEFINITIVE REPORT

"Re-educating" tumor-associated macrophages by targeting NF-{kappa}B

Thorsten Hagemann1, Toby Lawrence1, Iain McNeish2, Kellie A. Charles1, Hagen Kulbe1, Richard G. Thompson1, Stephen C. Robinson1, , and Frances R. Balkwill1

1 Centre for Cancer and Inflammation and 2 Centre for Molecular Oncology, Institute of Cancer and CR-UK Clinical Cancer Centre, Barts and The London School of Medicine and Dentistry, London EC1M 6BQ, UK

CORRESPONDENCE Thorsten Hagemann: t.hagemann{at}qmul.ac.uk

Abstract: The nuclear factor {kappa}B (NF-{kappa}B) signaling pathway is important in cancer-related inflammation and malignant progression. Here, we describe a new role for NF-{kappa}B in cancer in maintaining the immunosuppressive phenotype of tumor-associated macrophages (TAMs). We show that macrophages are polarized via interleukin (IL)-1R and MyD88 to an immunosuppressive "alternative" phenotype that requires I{kappa}B kinase β–mediated NF-{kappa}B activation. When NF-{kappa}B signaling is inhibited specifically in TAMs, they become cytotoxic to tumor cells and switch to a "classically" activated phenotype; IL-12high, major histocompatibility complex IIhigh, but IL-10low and arginase-1low. Targeting NF-{kappa}B signaling in TAMs also promotes regression of advanced tumors in vivo by induction of macrophage tumoricidal activity and activation of antitumor activity through IL-12–dependent NK cell recruitment. We provide a rationale for manipulating the phenotype of the abundant macrophage population already located within the tumor microenvironment; the potential to "re-educate" the tumor-promoting macrophage population may prove an effective and novel therapeutic approach for cancer that complements existing therapies.

T. Hagemann and T. Lawrence contributed equally to this work.

© 2008 Hagemann et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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