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

Copyright © 2008 by the Rockefeller University Press.


"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}

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 After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at

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