背景:特发性肺纤维化(IPF)患者普遍存在纵隔淋巴结肿大。缺乏调查这种现象是否反映特异性免疫激活的研究。
方法:分析纵隔淋巴结和肺组织中程序性细胞死亡-1(PD-1)/程序性细胞死亡配体-1(PD-L1)的表达。在第14天博莱霉素诱导的损伤后,在小鼠的气管支气管淋巴结中测量PD-1、PD-L1mRNA表达。最后,PD-1抑制剂的作用,pembrolizumab,在博来霉素诱导的肺纤维化中进行了研究。
结果:我们分析了33例患者的纵隔淋巴结(n=33,IPF:n=14,肺癌:n=10,合并IPF和肺癌:n=9)和219例患者的肺组织(n=219,IPF:123,对照:96)。PD-1表达增加,而PD-L1表达下降,IPF患者纵隔淋巴结与肺癌相比,IPF肺与对照肺相比。与盐水处理的动物相比,在第14天从博来霉素处理的小鼠分离的气管支气管淋巴结表现出增加的大小和更高的PD-1、PD-L1mRNA水平。Pembrolizumab减弱了博莱霉素诱导的肺纤维化,如Ashcroft评分降低和呼吸力学改善所示。
结论:与肺癌患者相比,IPF患者的纵隔淋巴结表现出差异表达谱,表明不同的免疫介导途径调节纤维发生和癌变。纵隔淋巴结中PD-1的表达与肺组织的表达一致。较低剂量的派姆单抗可能发挥抗纤维化作用。临床试验旨在基于纵隔淋巴结谱分析的内生型患者,并相应地实施靶向治疗,如PD-1抑制剂是非常期待的。
BACKGROUND: Mediastinal lymph node enlargement is prevalent in patients with idiopathic pulmonary fibrosis (IPF). Studies investigating whether this phenomenon reflects specific immunologic activation are lacking.
METHODS: Programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1) expression in mediastinal lymph nodes and lung tissues was analyzed. PD-1, PD-L1 mRNA expression was measured in tracheobronchial lymph nodes of mice following bleomycin-induced injury on day 14. Finally, the effect of the PD-1 inhibitor, pembrolizumab, in bleomycin-induced pulmonary fibrosis was investigated.
RESULTS: We analyzed mediastinal lymph nodes of thirty-three patients (n = 33, IPF: n = 14, lung cancer: n = 10, concomitant IPF and lung cancer: n = 9) and lung tissues of two hundred nineteen patients (n = 219, IPF: 123, controls: 96). PD-1 expression was increased, while PD-L1 expression was decreased, in mediastinal lymph nodes of patients with IPF compared to lung cancer and in IPF lungs compared to control lungs. Tracheobronchial lymph nodes isolated on day 14 from bleomycin-treated mice exhibited increased size and higher PD-1, PD-L1 mRNA levels compared to saline-treated animals. Pembrolizumab blunted bleomycin-induced lung fibrosis, as indicated by reduction in Ashcroft score and improvement in respiratory mechanics.
CONCLUSIONS: Mediastinal lymph nodes of patients with IPF exhibit differential expression profiles than those of patients with lung cancer indicating distinct immune-mediated pathways regulating fibrogenesis and carcinogenesis. PD-1 expression in mediastinal lymph nodes is in line with lung tissue expression. Lower doses of pembrolizumab might exert antifibrotic effects. Clinical trials aiming to endotype patients based on mediastinal lymph node profiling and accordingly implement targeted therapies such as PD-1 inhibitors are greatly anticipated.