Tissue MicroRNA Expression as a Predictor of Response to Immunotherapy in NSCLC Patients

Frontiers in Oncology

Sławomir Mańdziuk¹  Agnieszka Kolak¹  Tomasz Kubiatowski²  Elżbieta Starosławska²  Stanisław Kieszko²  Iwona Paśnik³  Justyna Szumiło³  Maciej Krzakowski⁴  Dariusz Kowalski⁴  Bożena Jarosz⁵  Daria Świniuch⁶  Rodryg Ramlau⁶  Janusz Milanowski⁷  Robert Kieszko⁷  Anna Grenda⁷  Paweł Krawczyk⁷  Izabela Chmielewska⁷  Justyna Błach⁷  Michał Szczyrek⁷  Kamila Wojas-Krawczyk⁷  Małgorzata Frąk⁷  Tomasz Kucharczyk⁷  Małgorzata Borowiec-Bar⁷  Marek Sawicki⁸  Katarzyna Reszka⁹  Kinga Krukowska⁹ 

[1] Department of Clinical Oncology and Chemotherapy, Medical University of Lublin, Lublin, Poland;Department of Clinical Oncology, Saint John of Dukla Oncology Centre of the Lublin Region, Lublin, Poland;Department of Clinical Pathomorphology, Medical University of Lublin, Lublin, Poland;Department of Lung and Chest Cancer, The Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Warsaw, Poland;Department of Neurosurgery and Paediatric Neurosurgery, Medical University of Lublin, Lublin, Poland;Department of Oncology, Poznan University of Medical Sciences, Poznań, Poland;Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland;Department of Thoracic Surgery, Medical University of Lublin, Lublin, Poland;Genetics and Immunology Institute of Lublin, Genim LLC, Lublin, Poland;

关键词: PD-L1;    immunotherapy;    microRNA;    non-small cell lung cancer;    SNP;    copy number variation;   

DOI  :  10.3389/fonc.2020.563613

来源: DOAJ

【 摘 要 】

IntroductionExpression 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.Materials and MethodsThe 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 PD-L1 mRNA expression. Copy number variation (CNV) of PD-L1 gene by qPCR and FISH methods were assessed. Two single nucleotide polymorphisms (SNPs) in promoter region of PD-L1 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.ResultsResponse 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).ConclusionThe miR-200b and miR-429 molecules in tumor cells seem to have greatest impact on the effectiveness of immunotherapy in NSCLC patients.

【 授权许可】

Unknown