Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer
Allyson G. McLoed,
Taylor P. Sherrill,
Dong-Sheng Cheng,
Wei Han,
Jamie A. Saxon,
Linda A. Gleaves,
Pingsheng Wu,
Vasiliy V. Polosukhin,
Michael Karin,
Fiona E. Yull,
Georgios T. Stathopoulos,
Vassilis Georgoulias,
Rinat Zaynagetdinov,
Timothy S. Blackwell
Affiliations
Allyson G. McLoed
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
Taylor P. Sherrill
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA
Dong-Sheng Cheng
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA
Wei Han
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA
Jamie A. Saxon
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
Linda A. Gleaves
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA
Pingsheng Wu
Department of Biostatistics, Vanderbilt University, Nashville, TN 37232, USA
Vasiliy V. Polosukhin
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA
Michael Karin
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Fiona E. Yull
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
Georgios T. Stathopoulos
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA
Vassilis Georgoulias
Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Crete 71110, Greece
Rinat Zaynagetdinov
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA
Timothy S. Blackwell
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
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.
