The Role of Nuclear Factor Kappa B in Myeloid Cells During Lung Carcinogenesis
Perry, Allyson Gail
Despite recent progress, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality in the United States and new therapeutic approaches are needed. Nuclear factor κB (NF-κB) is a master regulator of inflammatory signaling that is overexpressed in most solid tumors. Several mouse models of lung cancer have confirmed the requirement for NF-κB signaling in airway epithelial cells during lung tumorigenesis. However, despite these findings, inhibitors of NF-κB have been ineffective in treating NSCLC patients. Using genetic and pharmacologic inhibition of NF-κB signaling in murine lung cancer models, we found that blockade of NF-κB signaling in the myeloid inflammatory cell population paradoxically increases lung inflammation, airway epithelial cell proliferation, and lung tumorigenesis. We identified cathepsin G-mediated processing of IL-1β by neutrophils as a novel resistance mechanism of NSCLC to NF-κB inhibitors, and combined therapy with an NF-κB inhibitor and IL-1 receptor antagonist reduced tumorigenesis in mouse models of lung cancer. In NSCLC patients, plasma IL-1β concentration inversely correlated with progression-free survival and IL-1β levels were increased following treatment with an NF-κB inhibitor. These studies demonstrate that targeting common signaling pathways can have opposing effects in individual cell types during tumorigenesis; they support the use of rational, combined therapies to treat lung cancer.