Neutrophil-Derived IL-1beta Impairs the Efficacy of NF-kappaB Inhibitors against Lung Cancer

Although epithelial NF-kappaB signaling is important for lung carcinogenesis, NF-kappaB inhibitors are ineffective for cancer treatment. To explain this paradox, we studied mice with genetic deletion of IKKbeta in myeloid cells and found enhanced tumorigenesis in Kras(G12D) and urethane models of lung cancer. Myeloid-specific inhibition of NF-kappaB augmented pro-IL-1beta processing by cathepsin G in neutrophils, leading to increased IL-1beta and enhanced epithelial cell proliferation. Combined treatment with bortezomib, a proteasome inhibitor that blocks NF-kappaB activation, and IL-1 receptor antagonist reduced tumor formation and growth in vivo. In lung cancer patients, plasma IL-1beta levels correlated with poor prognosis, and IL-1beta increased following bortezomib treatment. Together, our studies elucidate an important role for neutrophils and IL-1beta in lung carcinogenesis and resistance to NF-kappaB inhibitors.

• McLoed, A. G.
• Sherrill, T. P.
• Cheng, D. S.
• Han, W.
• Saxon, J. A.
• Gleaves, L. A.
• Wu, P.
• Polosukhin, V. V.
• Karin, M.
• Yull, F. E.
• Stathopoulos, G. T.
• Georgoulias, V.
• Zaynagetdinov, R.
• Blackwell, T. S.