"Re-educating" tumor-associated macrophages by targeting NF-kappaB.
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.
Hagemann
Thorsten
T
Centre for Cancer and Inflammation, Institute of Cancer, Barts and The London School of Medicine and Dentistry, London EC1M 6BQ, UK. t.hagemann@qmul.ac.uk
Lawrence
Toby
T
McNeish
Iain
I
Charles
Kellie A
KA
Kulbe
Hagen
H
Thompson
Richard G
RG
Robinson
Stephen C
SC
Balkwill
Frances R
FR
D000818:Animals; D002454:Cell Differentiation; D006801:Humans; D007165:Immunosuppression Therapy; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D009369:Neoplasms / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction
D016328:NF-kappa B