UC San Diego

Lung cancer (LC) is the leading cause of cancer death worldwide. While smoking remains the predominant cause of LC, LC in never-smokers accounts for up to 25% of all LC incidents. Clinical Studies have shown that people diagnosed with a chronic inflammatory lung disease such as chronic obstructive pulmonary disease (COPD) and possibly asthma are at increased risk of LC. Previous studies in the lab have identified that chronic lung inflammation caused by long-term exposure to the allergen House Dust Mite (HDM) leads to the acceleration of LC in mice. This is due to an increase of a subtype of lung inflammation, in which the Nod-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome and interleukin-1 (IL-1β) signaling pathway is chronically activated in lung macrophages. The present study looked downstream of IL-1β signaling at the transcription factors RORγ and RORγt. Our results show that the pharmacological inhibition of RORγ/γt using digoxin decreased LC development in a KrasG12D-driven LC model. Additionally, we found that IL-1β signaling and RORγ inhibition do not affect LC cell proliferation and survival in vitro using the Lewis Lung Carcinoma (LLC) cells. Furthermore, the anti-tumor effect of digoxin is essentially inhibited in absence of T cells in Rag1 KO mice, suggesting that the observed effect is likely due to the inhibition of RORγt in Th17 cells and other RORγt-expressing immune cells (e.g., ILC3, NK cells) rather than a direct effect on LC cells.