Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer

Although epithelial NF-κB signaling is important for lung carcinogenesis, NF-κB inhibitors are ineffective for cancer treatment. To explain this paradox, we studied mice with genetic deletion of IKKβ in myeloid cells and found enhanced tumorigenesis in KrasG12D and urethane models of lung cancer. Myeloid-specific inhibition of NF-κB augmented pro-IL-1β processing by cathepsin G in neutrophils, leading to increased IL-1β and enhanced epithelial cell proliferation. Combined treatment with bortezomib, a proteasome inhibitor that blocks NF-κB activation, and IL-1 receptor antagonist reduced tumor formation and growth in vivo. In lung cancer patients, plasma IL-1β levels correlated with poor prognosis, and IL-1β increased following bortezomib treatment. Together, our studies elucidate an important role for neutrophils and IL-1β in lung carcinogenesis and resistance to NF-κB inhibitors. [Display omitted] •Inhibition of NF-κB signaling in myeloid cells enhances lung tumorigenesis•Carcinogen treatment induces IL-1β processing in neutrophils with NF-κB inhibition•NF-κB targeting with bortezomib increases IL-1β production in NSCLC patients•Combination therapy with bortezomib and IL-1R antagonist slows tumor growth in mice McLoed et al. show that inhibition of NF-κB signaling in myeloid cells augments lung tumorigenesis. Myeloid-specific or systemic NF-κB inhibition increases IL-1β production by neutrophils, which enhances lung tumor formation. These studies highlight an important resistance pathway that limits efficacy of NF-κB inhibitors.