LAUSR

Clinical and epidemiological evidence suggest that chronic infection and inflammation increase risk of lung cancer. Pseudomonas aeruginosa infection is frequently found in patients with chronic obstructive pulmonary disease (COPD) and is associated with increased lung inflammation and acute exacerbations. However, the mechanism of chronic bacterial infection-induced lung inflammation in promoting lung tumorigenesis remains unclear. To elucidate this mechanism, we established a murine lung cancer model by treating mice with or without recurrent lipopolysaccharides (LPS) from Pseudomonas aeruginosa in combination with nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Interestingly, combined LPS and NNK exposure significantly increased tumor number, tumor incidence, and tumor area compared to NNK treatment alone. In addition, the inflammatory cell counts in the bronchoalveolar lavage (BAL) including macrophages, neutrophils, and lymphocytes were significantly increased in the LPS/NNK treatment group. The BAL fluid of chemokines/cytokines, as analyzed by luminex assays, revealed higher levels of IL-17, CXCL10, GM-CSF, G-CSF, MIP-1a, and KC in LPS/NNK than in NNK treatment group. Flow cytometry analysis of the mouse lung tissue revealed that combined LPS and NNK exposure significantly increased CD4+ T cells including Th1, Th17, and Tregs and myeloid-derived suppressor cells recruitment in the lung. Real-time polymerase chain reaction of mouse lung tissue showed T cell exhaustion related genes, including Pdcd1, Ctla-4, Tim-3, Lag-3, and Foxp3, were significantly upregulated in the LPS/NNK treatment than NNK treatment. Moreover, immunohistochemical staining of LPS/NNK-exposed lung tumors showed higher PD-L1 expression than NNK-exposed lung tumors. Our data suggest that chronic LPS exposure-promoted and NNK-induced lung tumorigenesis is associated with immunosuppressive tumor microenvironment. The changes include recruitment of Tregs and MDSCs, increased T cell exhaustion, and upregulated PD-1/PD-L1 pathway, which may be used as the therapeutic target for chronic inflammation-associated lung cancer treatment. Citation Format: Chia-Hsin Liu, Kong Chen, Yuanpu Di. Lipopolysaccharide-induced chronic inflammation promotes lung tumorigenesis in the context of an immunosuppressive microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1094.