Re-educating tumor-associated macrophages by targeting NF-κB

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 beta-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-12 high, major histocompatibility complex II high, but IL-10 low and arginase-1 low. 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.