Correlation of plasma exosomal microRNAs with the efficacy of immunotherapy inEGFR/ALKwild-type advanced non-small cell lung cancer

Abstract

BackgroundImmunotherapy has become an important treatment option for patients with advanced non-small cell lung cancer (NSCLC). At present, none of these existing biomarkers can effectively stratify true responders and there is an urgent need for identifying novel biomarkers. Exosomes derived from the serum of patients with cancer have been proven to be reliable markers for cancer diagnosis. Here, we explored the possibility of using plasma-derived exosomal microRNAs as potential biomarkers for optimal selection of patients with advancedEGFR/ALKnegative NSCLC to immunotherapy.MethodsFrom June 2017 to February 2019, 30 patients with advancedEGFR/ALKwild-type (WT) NSCLC who received PD-1/PD-L1 inhibitors were enrolled. The efficacy evaluation was conducted after every three cycles of treatment according to RECIST 1.1. Plasma samples of these patients were collected before the administration of PD-1/PD-L1 inhibitors as baseline, and after every three cycles if the patients achieved partial response (PR) or complete response. Plasma from seven healthy individuals was also collected as normal control. Exosomes were prepared by ultracentrifugation followed by total RNA extraction, and exosome-derived miRNAs were profiled using small RNA next-generation sequencing followed by differential expression analysis.ResultsIn order to identify biomarker for better response, all five patients who achieved PR and four patients with progressive disease (PD) at efficacy evaluation were included for differential expression analysis. Based on unsupervised hierarchical clustering, exosomal miRNA expression profile was significantly altered in patients with NSCLC compared with normal controls with a total of 155 differentially expressed exosomal miRNAs. Interestingly, hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified significantly upregulated in the PD groups compared with the PR group at baseline before the treatment. In addition, we identified that hsa-miR-125b-5p, a T-cell suppressor, showed a trend of increased expression in the PD group at baseline and was significantly downregulated in the post-treatment plasma exosomes compared with pre-treatment samples of the PR patients.ConclusionPatients with NSCLC represent unique plasma exosomal miRNA profiles. Hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified as potential biomarkers for predicting the efficacy of immunotherapy in advanced NSCLCs. When T-cell suppressor hsa-miR-125b-5p was downregulated during the treatment, the patients may obtain increased T-cell function and respond well to immunotherapy.

Precision Medicine for NSCLC in the Era of Immunotherapy: New Biomarkers to Select the Most Suitable Treatment or the Most Suitable Patient

“…The authors identified three members of the miRNA-320 family (miRNA-320b, miRNA-320c and miRNA-320d) as potential biomarkers for predicting the efficacy of immunotherapy in advanced NSCLCs. In addition, the authors showed that miRNA-125b-5p was downregulated in the post-treatment exosome plasma compared to baseline samples of the patients experiencing a partial response [181].…”

Exosome-based immunotherapy: a promising approach for cancer treatment

“…Among them, it was found that low levels of exosome-derived hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b may indicate the better efficacy of PD-1/PD-L1 immunotherapy in advanced NSCLCs. In addition, when hsa-miR-125b-5p, a T-cell suppressor in exosomes, is downregulated during immunotherapy, NSCLC patients may gain enhanced T-cell function and respond well [154].…”

An miRNA signature associated with tumor mutation burden in endometrial cancer

“…However, the role of miRNAs in personalized cancer treatment has been not fully elucidated yet. A study conducted by Peng et al [ 23 ] revealed that three miRNAs (hsa-miR-320d, hsa-miR-320c, hsa-miR-320b) might predict immunotherapy response in non-small cell lung cancer.…”