"Re-educating" tumor-associated macrophages by targeting NF-kappaB

Hagemann, T., Lawrence, T., Mcneish, I. , Charles, K.A., Kulbe, H., Thompson, R.G., Robinson, S.C. and Balkwill, F.R. (2008) "Re-educating" tumor-associated macrophages by targeting NF-kappaB. Journal of Experimental Medicine, 205(6), pp. 1261-1268. (doi: 10.1084/jem.20080108)

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Abstract

The nuclear factor kappaB (NF-kappaB) signaling pathway is important in cancer-related inflammation and malignant progression. Here, we describe a new role for NF-kappaB 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 IkappaB kinase beta-mediated NF-kappaB activation. When NF-kappaB signaling is inhibited specifically in TAMs, they become cytotoxic to tumor cells and switch to a "classically" activated phenotype; IL-12(high), major histocompatibility complex II(high), but IL-10(low) and arginase-1(low). Targeting NF-kappaB 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Mcneish, Professor Iain
Authors: Hagemann, T., Lawrence, T., Mcneish, I., Charles, K.A., Kulbe, H., Thompson, R.G., Robinson, S.C., and Balkwill, F.R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Experimental Medicine
Publisher:Rockefeller University Press
ISSN:1540-9538
Published Online:19 May 2008
Copyright Holders:Copyright © 2008 The Authors
First Published:First published in Journal of Experimental Medicine 206(6):1261-1268
Publisher Policy:Reproduced under a Creative Commons License

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