Toll-Like Receptor 7 Mediates Inflammation Resolution and Inhibition of Angiogenesis in Non-Small Cell Lung Cancer

SIMPLE SUMMARY: The progression of cancer is strictly linked to the formation of new blood vessels responsible for nutrition supply of the tumor. We identified TLR7 as an inhibitor of lung cancer vascularization. TLR7 is part of a large family of immune receptors that function as “sensors” of pathogen- and damage-derived signals. We found that TLR7 exerts antitumor functions in non-small cell lung cancer by inducing the production of specific molecules with inhibitory properties against new blood vessel formation. These molecules are known as specialized pro-resolving mediators (SPMs) and are derived from ω-3 and ω-6 fatty acids. We believe that the results obtained suggest novel potential targets and strategies to treat lung cancer. ABSTRACT: Pattern recognition receptors (PRR) promote inflammation but also its resolution. We demonstrated that a specific PRR—formyl peptide receptor 1 (FPR1)—sustains an inflammation resolution response with anti-angiogenic and antitumor potential in gastric cancer. Since toll-like receptor 7 (TLR7) is crucial in the physiologic resolution of airway inflammation, we asked whether it could be responsible for pro-resolving and anti-angiogenic responses in non-small cell lung cancer (NSCLC). TLR7 correlated directly with pro-resolving and inversely with angiogenic mediators in NSCLC patients, as revealed by a publicly available RNAseq analysis. In NSCLC cells, depletion of TLR7 caused an upregulation of angiogenic mediators and a stronger vasculogenic response of endothelial cells compared to controls, assessed by qPCR, ELISA, protein array, and endothelial cell responses. TLR7 activation induced the opposite effects. TLR7 silencing reduced, while its activation increased, the pro-resolving potential of NSCLC cells, evaluated by qPCR, flow cytometry, and EIA. The increased angiogenic potential of TLR7-silenced NSCLC cells is due to the lack of pro-resolving mediators. MAPK and STAT3 signaling are responsible for these activities, as demonstrated through Western blotting and inhibitors. Our data indicate that TLR7 sustains a pro-resolving signaling in lung cancer that inhibits angiogenesis. This opens new possibilities to be exploited for cancer treatment.