Inflammation synergistically promotes cigarette smoke carcinogen-induced lung tumorigenesis and determines immunotherapy efficacy

Abstract

Abstract Chronic obstructive pulmonary disease (COPD) is a chronic lung inflammatory disease with an increased risk of lung cancer. Pseudomonas aeruginosa (PA) are opportunistic bacteria frequently found in patients with COPD, and associated with increased lung inflammation and acute exacerbations. The impacts of COPD-related inflammation, especially those induced by the PA-produced lipopolysaccharides (LPS), on lung tumorigenesis and the efficacy of immune checkpoint blockades remain poorly understood. In this study, we established a novel murine lung cancer model by treating mice with cigarette smoke carcinogen nitrosamine (NNK) combined with recurrent LPS exposure. LPS-mediated chronic inflammation in NNK-treated mice generates an immunosuppressive microenvironment characterized by the accumulation of myeloid-derived suppressive cells (MDSCs) and regulatory T cells, induced T-cell exhaustion, and enhanced PD-1/PD-L1 activity that resulted in synergistic increases of lung tumorigenesis than NNK treatment alone (>8-fold increase in tumor numbers, P<0.0001). Immunotherapy using anti-PD-1 antibody or anti-Ly6G antibody (to deplete MDSCs) alone reduced tumor growth, and in combination further enhanced the anti-tumor activity. We also identified immune gene signatures from the RNA transcript expression data of our murine cancer model and the published datasets of PD-1 blockade, which effectively predicted treatment responses and survival outcome in cohorts with immunotherapy and conventional treatments. Our results indicate that LPS-mediated chronic inflammation creates a favorable immunosuppressive microenvironment for tumor progression and correlates with the efficacy of anti-PD-1 treatment.