The nuclear factor B (NF-B) signaling pathway is important in cancer-related infl ammation and malignant progression. Here, we describe a new role for NF-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 B kinase ␤ -mediated NF-B activation. When NF-B signaling is inhibited specifi cally 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-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.

Constitutive expression of the inflammatory cytokine tumor

Purpose: We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network.Experimental Design: We combined preclinical and in silico experiments with a phase 2 clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer.