Lipopolysaccharide-Mediated Chronic Inflammation Promotes Tobacco Carcinogen–Induced Lung Cancer and Determines the Efficacy of Immunotherapy

Abstract

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.

Potential Reasons for Unresponsiveness to Anti-PD1 Immunotherapy in Young Patients with Advanced Melanoma

“…This might partially explain the age-favored clinical benefit of anti-PD1 treatment in older people as proteobacteria-derived LPS traditionally may drive immune infiltration to the TME, which may enhance treatment efficacy. An example of how bacteria may influence TME comes from a recent study showing that Pseudomonas aeruginosa LPS in mice with lung cancer enhances inflammatory cell recruitment throughout the tumor and induces PD1/PDL1 expression which leads to efficient anti-PD1 responses [95].…”

Relationship between Lung Carcinogenesis and Chronic Inflammation in Rodents

“…In C57BL/6 mice, tumorigenesis was induced by BaP and lipopolysaccharide (LPS), a potent proinflammatory agent found in tobacco and tobacco smoke [81,132]. In an NNK plus LPS model, LPS-mediated chronic inflammation induced T-cell exhaustion, upregulated 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 and regulatory T cells [133]. Mice treated with NTCU plus LPS showed significantly increased expression of the inflammatory cytokines IL-1α, IL-6, and TNF-α [81].…”

Nicotine promotes chronic obstructive pulmonary disease via inducing pyroptosis activation in bronchial epithelial cells

“…Inflammation and cell death are the two critical pathological mechanisms of COPD ( 13 , 14 ). Enhanced cell death can be observed during the destruction of lung tissue in both humans and mice ( 14 , 15 ).…”