Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Cancer Res. 2021 Jan 1;81(1):144-157. doi: 10.1158/0008-5472.CAN-20-1994. Epub 2020 Oct 29.
Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that is associated with increased risk of lung cancer. (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.
慢性阻塞性肺疾病（COPD）是一种炎症性疾病，与肺癌风险增加有关。（PA）感染在 COPD 患者中很常见，会增加肺部炎症和急性加重。然而，PA 诱导的炎症对肺肿瘤发生和免疫检查点阻断的疗效的影响尚不清楚。在这项研究中，我们通过单独或联合使用烟草致癌剂亚硝胺 4-（甲基亚硝氨基）-1-（3-吡啶基）-1-丁酮（NNK）和 PA-脂多糖（LPS）处理 FVB/NJ 雌性小鼠，启动了肺癌小鼠模型。LPS 介导的慢性炎症诱导 T 细胞耗竭，增加了程序性细胞死亡-1（PD-1）/程序性细胞死亡配体-1（PD-L1）轴，并通过以髓系来源的抑制细胞（MDSC）和调节性 T 细胞积累为特征的免疫抑制微环境增强了 NNK 诱导的肺癌发生。抗 PD-1 抗体治疗减少了 10 周 LPS 治疗的 NNK/LPS 处理小鼠中的肿瘤，但当 LPS 暴露延长至 16 周时，未能抑制肿瘤生长。单独用抗 Ly6G 抗体治疗联合 MDSC 耗竭可减少肿瘤生长；与抗 PD-1 抗体联合使用时，可进一步增强 16 周 NNK/LPS 处理小鼠的抗肿瘤活性。从 PD-1 阻断的人类肺癌数据集鉴定了免疫基因特征，这些特征预测了治疗反应和生存结果，并与小鼠模型重叠。这项研究表明，LPS 介导的慢性炎症为肿瘤进展创造了有利的免疫抑制微环境，与小鼠中抗 PD-1 治疗的疗效相关。免疫基因特征与人类和小鼠肺癌重叠，为接受免疫治疗的患者提供了潜在的预测标志物。意义：本研究确定了一个免疫基因特征，可预测接受免疫检查点阻断治疗的烟草致癌物诱导的肺癌患者的治疗反应和生存。
