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

Abstract

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.

circHUWE1 Exerts an Oncogenic Role in Inducing DDP-Resistant NSCLC Progression Depending on the Regulation of miR-34a-5p/TNFAIP8

“…However, innate or acquired pharmacological resistance represents important obstacles to overcome. As well-documented, noncoding RNAs including circular RNAs (circRNAs) and microRNAs (miRNAs) are one of the pharmacological resistance mechanisms in tumor cells [8,9]. Cisplatin (DDP) is the backbone of first-line chemotherapy for NSCLC [10].…”

Potential of the miR-200 Family as a Target for Developing Anti-Cancer Therapeutics

“…Many studies have reported the decreased expression of the miR-200 family in cancer tissues [ 18 , 19 ], and anti-cancer drug-resistant cancer cells [ 93 ]. The expression levels of miR-200 family miRNAs were shown to predict responses to anti-cancer therapeutics [ 19 , 20 , 21 , 22 , 23 , 24 ]. Thus, miR-200 family miRNAs can be a target for anti-cancer drug development.…”

“…High levels of the miR-200 family were strongly associated with better survival of bladder cancer patients [ 23 ]. The high expression of miR-200b was correlated with better responses of lung cancer patients to immunotherapy involving anti-PD-l antibodies such as pembrolizumab [ 24 ].…”

Multi-Omics Approaches for the Prediction of Clinical Endpoints after Immunotherapy in Non-Small Cell Lung Cancer: A Comprehensive Review

“…Several studies have focused on the value of micro RNAs and non-coding RNAs for the prediction of responses to ICIs. Several tissue-extracted microRNAS such as miR-200b and miR-508 appear as positively correlated with the response to ICIs, while others such as miR-429 are negative biomarkers [ 72 ]; however, this did not remain significant after multivariate analysis when compared to PD-L1 expression. Based on a large cohort of NSCLC patients, a model combining seven non-coding RNAs significantly stratified patients into immune-cold and immune-hot cohorts, remained independent from other clinical/biological features and could complete the PD-L1 expression as a biomarker [ 73 ].…”