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

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Title: "Re-educating" tumor-associated macrophages by targeting NF-kappa B
Authors: Hagemann, T
Lawrence, T
McNeish, I
Charles, KA
Kulbe, H
Thompson, RG
Robinson, SC
Balkwill, FR
Item Type: Journal Article
Abstract: The nuclear factor κB (NF-κB) signaling pathway is important in cancer-related inflammation and malignant progression. Here, we describe a new role for NF-κB 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 IκB kinase β–mediated NF-κB activation. When NF-κB 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-κB 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.
Issue Date: 9-Jun-2008
URI: http://hdl.handle.net/10044/1/55474
DOI: https://dx.doi.org/10.1084/jem.20080108
ISSN: 0022-1007
Publisher: Rockefeller Univ Press
Start Page: 1261
End Page: 1268
Journal / Book Title: Journal of Experimental Medicine
Volume: 205
Issue: 6
Copyright Statement: © 2008 Hagemann et al. The Rockefeller University Press.
Keywords: Science & Technology
Life Sciences & Biomedicine
Immunology
Medicine, Research & Experimental
Research & Experimental Medicine
NITRIC-OXIDE SYNTHASE
OVARIAN-CANCER CELLS
MOUSE MODEL
INFLAMMATION
ALPHA
ACTIVATION
LIPOPOLYSACCHARIDE
IMMUNOTHERAPY
INVASIVENESS
PROGRESSION
Animals
Cell Differentiation
Humans
Immunosuppression
Macrophages
Mice
NF-kappa B
Neoplasms
Phenotype
Signal Transduction
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Division of Cancer
Faculty of Medicine



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