Gram-positive pneumonia augments non-small cell lung cancer metastasis via host toll-like receptor 2 activation

Surgical resection of early stage nonsmall cell lung cancer (NSCLC) is necessary for cure. However, rates of postoperative bacterial pneumonias remain high and may confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory cascade by recognizing microbial products at the surface of numerous cell types in the lung; however, little is known about how host TLRs influence NSCLC metastasis. TLR2 recognizes gram-positive bacterial cell wall components activating innate immunity. We demonstrate that lower respiratory tract infection with Streptococcus pneumonia augments the formation of murine H59 NSCLC liver metastases in C57BL/6 mice through host TLR2 activation. Infected mice demonstrate increased H59 and human A549 NSCLC adhesion to hepatic sinusoids in vivo compared with noninfected controls, a response that is significantly diminished in TLR2 knock-out mice. Intra-tracheal injection of purified TLR2 ligand lipoteichoic acid into mice similarly augments in vivo adhesion of H59 cells to hepatic sinusoids. Additionally, H59 and A549 NSCLC cells incubated with bronchoepithelial conditioned media show increased cell adhesion to extracellular matrix components in vitro and hepatic sinusoids in vivo in a manner that is dependent on bronchoepithelial TLR2 activation and interleukin-6 secretion. TLR2 is therefore a potential therapeutic target for gram-positive pneumonia-driven NSCLC metastasis. What's new? Toll-like receptors (TLRs) serve a role in microbial recognition at the cell surface in the lung. In non-small cell lung cancer (NSCLC), however, TLRs are suspected of contributing to post-operative bacterial pneumonia, which potentially increases metastatic risk. This study demonstrates in mice that the presence of Streptococcus pneumonia in the lower respiratory tract in fact augments NSCLC liver metastasis. By comparison, metastases were diminished in TLR2 knockout animals, while intra-tracheal administration of TLR2-activating ligand triggered metastasis following H59 cell injection in wild-type animals. The findings suggest that TLR2 is a promising target for the treatment of gram-positive pneumonia-associated NSCLC metastasis.