Chronic obstructive pulmonary disease (
COPD) is an inflammatory disease that is associated with increased risk of
lung cancer. Pseudomonas aeruginosa (PA)
infections are frequent in patients with
COPD, which increase
lung inflammation and acute exacerbations. However, the influences of PA-induced
inflammation on lung
tumorigenesis and the efficacy of
immune checkpoint blockade remain unknown. In this study, we initiated a murine model of
lung cancer by treating FVB/NJ female mice with tobacco
carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) alone or in combination with PA-
lipopolysaccharide (LPS). LPS-mediated chronic
inflammation induced T-cell exhaustion, increased the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis, and enhanced NNK-induced lung
tumorigenesis through an immunosuppressive microenvironment characterized by accumulation of myeloid-derived suppressive cells (MDSC) and regulatory T cells. Anti-PD-1 antibody treatment reduced
tumors in NNK/LPS-treated mice with a 10-week LPS treatment but failed to inhibit
tumor growth when LPS exposure was prolonged to 16 weeks. Anti-Ly6G antibody treatment coupled with depletion of MDSC alone reduced
tumor growth; when combined with anti-PD-1 antibody, this treatment further enhanced antitumor activity in 16-week NNK/LPS-treated mice. Immune gene signatures from a human
lung cancer dataset of PD-1 blockade were identified, which predicted treatment responses and survival outcome and overlapped with those from the mouse model. This study demonstrated that LPS-mediated chronic
inflammation creates a favorable immunosuppressive microenvironment for
tumor progression and correlates with the efficacy of anti-PD-1 treatment in mice. Immune gene signatures overlap with human and mouse lung
tumors, providing potentially predictive markers for patients undergoing
immunotherapy. SIGNIFICANCE: This study identifies an immune gene signature that predicts treatment responses and survival in patients with tobacco
carcinogen-induced
lung cancer receiving
immune checkpoint blockade therapy.