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SPRING 2021 ARTICLE - DR. George Leikauf AND DR. Peter Di

Lipopolysaccharide-Mediated Chronic InflammationPromotes Tobacco Carcinogen–Induced Lung Cancerand Determines the Efficacy of Immunotherapy

Chronic obstructive pulmonary disease (COPD) is an inflam-matory disease that is associated with increased risk of lung cancer.Pseudomonas aeruginosa(PA) infections are frequent inpatients with COPD, which increase lung inflammation andacute exacerbations. However, the influences of PA-induced inflam-mation on lung tumorigenesis and the efficacy of immune check-point blockade remain unknown. In this study, we initiated amurine 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 inflammationinduced T-cell exhaustion, increased the programmed cell death-1(PD-1)/programmed cell death ligand-1 (PD-L1) axis, and enhancedNNK-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-weekLPS treatment but failed to inhibit tumor growth when LPS exposure was prolonged to 16 weeks. Anti-Ly6G antibody treatment coupled with depletion of MDSCalone reduced tumor growth; when combinedwith anti–PD-1 antibody, this treatment further enhanced antitumoractivity 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. Immunegene 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 check-point blockade therapy.


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