Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA.
Carcinogenesis. 2020 Nov 13;41(11):1518-1528. doi: 10.1093/carcin/bgaa059.
Chronic obstructive pulmonary disease (COPD) is a significant risk factor for lung cancer. One potential mechanism through which COPD contributes to lung cancer development could be through generation of an immunosuppressive microenvironment that allows tumor formation and progression. In this study, we compared the status of immune cells and immune checkpoint proteins in lung tumors induced by the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) or NNK + lipopolysaccharide (LPS), a model for COPD-associated lung tumors. Compared with NNK-induced lung tumors, NNK+LPS-induced lung tumors exhibited an immunosuppressive microenvironment characterized by higher relative abundances of PD-1+ tumor-associated macrophages, PD-L1+ tumor cells, PD-1+ CD4 and CD8 T lymphocytes and FOXP3+ CD4 and CD8 T lymphocytes. Also, these markers were more abundant in the tumor tissue than in the surrounding 'normal' lung tissue of NNK+LPS-induced lung tumors. PD-L1 expression in lung tumors was associated with IFNγ/STAT1/STAT3 signaling axis. In cell line models, PD-L1 expression was found to be significantly enhanced in phorbol-12-myristate 13-acetate activated THP-1 human monocytes (macrophages) treated with LPS or incubated in conditioned media (CM) generated by non-small cell lung cancer (NSCLC) cells. Similarly, when NSCLC cells were incubated in CM generated by activated THP-1 cells, PD-L1 expression was upregulated in EGFR- and ERK-dependent manner. Overall, our observations indicate that COPD-like chronic inflammation creates a favorable immunosuppressive microenvironment for tumor development and COPD-associated lung tumors might show a better response to immune checkpoint therapies.
慢性阻塞性肺疾病（COPD）是肺癌的一个重要危险因素。COPD 促进肺癌发展的一个潜在机制可能是通过产生免疫抑制微环境，从而允许肿瘤形成和进展。在这项研究中，我们比较了烟草烟雾致癌物 4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）或 NNK+脂多糖（LPS）诱导的肺癌中免疫细胞和免疫检查点蛋白的状态，NNK+LPS 是 COPD 相关肺癌的模型。与 NNK 诱导的肺癌相比，NNK+LPS 诱导的肺癌表现出免疫抑制微环境的特征，其特点是 PD-1+肿瘤相关巨噬细胞、PD-L1+肿瘤细胞、PD-1+CD4 和 CD8 T 淋巴细胞以及 FOXP3+CD4 和 CD8 T 淋巴细胞的相对丰度较高。此外，这些标志物在 NNK+LPS 诱导的肺癌的肿瘤组织中比在周围的“正常”肺组织中更为丰富。肺癌中的 PD-L1 表达与 IFNγ/STAT1/STAT3 信号轴有关。在细胞系模型中，发现 PD-L1 表达在 LPS 处理或非小细胞肺癌（NSCLC）细胞产生的条件培养基（CM）孵育的佛波醇-12-肉豆蔻酸 13-乙酸激活的 THP-1 人单核细胞（巨噬细胞）中显著增强。同样，当 NSCLC 细胞在激活的 THP-1 细胞产生的 CM 中孵育时，PD-L1 表达以 EGFR 和 ERK 依赖性方式上调。总的来说，我们的观察表明，COPD 样慢性炎症为肿瘤发展创造了有利的免疫抑制微环境，COPD 相关的肺癌可能对免疫检查点治疗有更好的反应。
