Abstract A32: Mechanistic Dissection of Lung Cancer Promotion by Airway Inflammation

Abstract

Abstract Cigarette smoking is the principal cause of lung carcinogenesis, however, smokers with chronic obstructive pulmonary disease (COPD) have an increased risk of lung cancer (3 to 10 fold) compared to smokers with comparable cigarette exposure but without COPD. Histopathologic studies have clearly demonstrated lung inflammation in COPD, and it persists even after cessation of cigarette smoking. These facts suggest a strong link between COPD-related airway inflammation and lung cancer promotion independent of smoking but the precise mechanistic link is not known. We developed a COPD-like mouse model of airway inflammation through repeated aerosol challenge to a lysate of non-typeable Haemophilus influenzae (NTHi) which commonly colonizes the airways of COPD patients. Then, we showed that this type of airway inflammation, but not asthma-like airway inflammation, promotes lung cancer in a K-ras mutant mouse model of lung cancer (CC-LR). This was associated with NF-kB pathway activation, and up-regulation of its downstream target genes, including IL-6 and T helper 17 (Th17) response. Therefore, we studied the role of NF-kB in lung cancer promotion by targeting its expression in airway epithelium. CC-LR mice were crossed with IKK-βf/f mice to develop a mouse with lack of NF-kB activity in airway secretory cells (CC-LR-IKKβ mice). NF-kB deficiency in the airway epithelium changed the bronchoalveolar lavage fluid (BALF) cellular component (mostly reduction in macrophage number) of the CC-LR mice, and resulted in a ∼70% (3.4-fold) reduction in lung surface tumor number compared to age and sex matched control CC-LR mice. It also significantly reduced the number of visible tumors on the lung surface of the CC-LR mice by >60% (2.6-fold) after inducing COPD-like airway inflammation using weekly NTHi exposure for 8 weeks. We then genetically ablated IL-6 in the CC-LR mice. Lack of IL-6 did not change the BALF inflammatory cell component of the CC-LR mice. However, it not only inhibited intrinsic lung cancer development (1.7-fold, 41%), but also inhibited the promoting effect of extrinsic NTHi-induced COPD-like airway inflammation (2.6-fold, 62%) on lung carcinogenesis, suggesting a role for IL-6 mediated epithelial cell signaling in tumor promotion by COPDlike airway inflammation. This is under further investigation by our group. IL-6 is required for differentiation of Th17 cells from naive T cells. Th17 cells mostly produce IL-17A, and IL-17F. These both bind to the IL-17 receptor (IL-17R), and IL-17R signaling is required for lung CXC chemokine expression and neutrophil recruitment, however, we found that only the IL-17R KO and IL-17A KO but not IL-17F KO mice showed lower levels of neutrophilic influx into the BALF and less inflammatory cell infiltration in lung tissue in response to NTHi. Furthermore, IL-17A induces more production of IL-6 by epithelial cells. So, CC-LR mice were crossed with IL-17A KO mice. Lack of IL-17A resulted in a ∼70% (3.4-fold) reduction in lung surface tumor number compared to age and sex matched control CC-LR mice. It also significantly reduced the number of visible tumors on the lung surface of the CCLR mice by ∼54% (2.2-fold) after inducing COPD-like airway inflammation using weekly NTHi exposure for 4 weeks from the age of 10 weeks. We conclude that airway inflammation through NF-kB mediated activation of the IL-6/Th17 signaling pathway promotes lung carcinogenesis.