Grenda Anna, Krawczyk Paweł, Błach Justyna, Chmielewska Izabela, Kubiatowski Tomasz, Kieszko Stanisław, Wojas-Krawczyk Kamila, Kucharczyk Tomasz, Jarosz Bożena, Paśnik Iwona, Borowiec-Bar Małgorzata, Frąk Małgorzata, Kieszko Robert, Szczyrek Michał, Reszka Katarzyna, Krukowska Kinga, Kolak Agnieszka, Mańdziuk Sławomir, Kowalski Dariusz, Sawicki Marek, Świniuch Daria, Starosławska Elżbieta, Ramlau Rodryg, Szumiło Justyna, Krzakowski Maciej, Milanowski Janusz
Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland.
Department of Clinical Oncology, Saint John of Dukla Oncology Centre of the Lublin Region, Lublin, Poland.
Front Oncol. 2021 Feb 8;10:563613. doi: 10.3389/fonc.2020.563613. eCollection 2020.
Expression of PD-L1 protein on tumor cells, which is so far the only validated predictive factor for immunotherapy, is regulated by epigenetic and genetic factors. Among the most important ones that regulate gene expression are microRNAs.
The study included 60 patients with NSCLC who underwent first or second line immunotherapy with pembrolizumab or nivolumab. FFPE materials were collected before the start of immunotherapy. We examined relative expression of microRNAs (miR-141, miR-200a, miR-200b, miR-200c, miR-429, miR-508-3p, miR-1184, miR-1255a) and mRNA expression. Copy number variation (CNV) of gene by qPCR and FISH methods were assessed. Two single nucleotide polymorphisms (SNPs) in promoter region of gene (rs822335 and rs822336) were examined. Expression of PD-L1 protein on tumor cells was assessed by immunohistochemistry (IHC). The response rate to immunotherapy and progression free survival (PFS) measured in weeks and overall survival (OS) measured in months from the start of immunotherapy were evaluated.
Response to immunotherapy was observed in nine patients (15%, including one complete response), disease stabilization in 22 patients (36.7%), and progression in 29 patients (48.3%). Significantly higher (p=0.015) expression of miR-200b and significantly lower (p=0.043) expression of miR-429 were observed in responders compared to patients who did not respond to immunotherapy. The median PFS in the whole group of patients was 16 weeks, and the median OS was 10.5 month. In univariate analysis, the median PFS was significantly higher in patients with high miR-200b expression (HR=0.4253, 95%CI: 0.1737-1.0417, p=0.05) and high miR-508 expression (HR=0.4401, 95%CI: 0.1903-1.0178, p=0.05) and with low expression of miR-429 (HR=0.1288, 95%CI: 0.01727-0.9606, p=0.0456) compared to patients with low and high expression of these molecules, respectively. The median OS was higher in patients with low expression of miR-429 (HR=0,6288, 95%CI: 0,3053-1,2949, p=0.06) compared with patients with high expression of this microRNA. In multivariate analysis, we found that patients with PD-L1 expression on ≥1% of tumor cells compared to patients without PD-L1 expression on cancer cells had a significantly lower risk of progression (HR=0.3857, 95%CI: 0.1612-0.9226, p=0.0323) and death (HR=0.377, 95%CI: 0.1636-0.8688, p=0.022).
The miR-200b and miR-429 molecules in tumor cells seem to have greatest impact on the effectiveness of immunotherapy in NSCLC patients.
肿瘤细胞上PD-L1蛋白的表达受表观遗传和遗传因素调控，是目前免疫治疗唯一经过验证的预测因子。在调控基因表达的最重要因素中，微小RNA（miRNA）是其中之一。
本研究纳入60例接受帕博利珠单抗或纳武利尤单抗一线或二线免疫治疗的非小细胞肺癌（NSCLC）患者。在免疫治疗开始前收集福尔马林固定石蜡包埋（FFPE）材料。我们检测了微小RNA（miR-141、miR-200a、miR-200b、miR-200c、miR-429、miR-508-3p、miR-1184、miR-1255a）的相对表达以及信使核糖核酸（mRNA）表达。通过定量聚合酶链反应（qPCR）和荧光原位杂交（FISH）方法评估基因的拷贝数变异（CNV）。检测基因启动子区域的两个单核苷酸多态性（SNP，rs822335和rs822336）。通过免疫组织化学（IHC）评估肿瘤细胞上PD-L1蛋白的表达。评估免疫治疗的缓解率以及从免疫治疗开始计算的以周为单位的无进展生存期（PFS）和以月为单位的总生存期（OS）。
9例患者（15%，包括1例完全缓解）对免疫治疗有反应，22例患者（36.7%）疾病稳定，29例患者（48.3%）病情进展。与未对免疫治疗产生反应的患者相比，反应者中miR-200b的表达显著更高（p=0.015），而miR-429的表达显著更低（p=0.043）。全组患者的中位PFS为16周，中位OS为10.5个月。在单因素分析中，与这些分子低表达和高表达的患者相比，miR-200b高表达（风险比[HR]=0.4253，95%置信区间[CI]：0.1737 - 1.0417，p=0.05）、miR-508高表达（HR=0.4401，95%CI：0.1903 - 1.0178，p=0.05）以及miR-429低表达（HR=0.1288，95%CI：0.01727 - 0.9606，p=0.0456）的患者中位PFS显著更高。与该微小RNA高表达的患者相比，miR-429低表达的患者中位OS更高（HR=0.6288，95%CI：0.3053 - 1.2949，p=0.06）。在多因素分析中，我们发现肿瘤细胞上PD-L1表达≥1%的患者与癌细胞无PD-L1表达的患者相比，疾病进展风险显著更低（HR=0.3857，95%CI：0.1612 - 0.9226，p=0.0323），死亡风险也显著更低（HR=0.377，95%CI：0.1636 - 0.8688，p=0.022）。
肿瘤细胞中的miR-200b和miR-429分子似乎对NSCLC患者免疫治疗的有效性影响最大。
Zotero 插件