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eSymposia | Advances in Cancer Immunotherapy


Expression of Non-Coding RNA Genes in Cancer Patients Treated with Immune-Checkpoint Inhibitors


Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

Description

Expression of Non-Coding RNA Genes in Cancer Patients Treated with Immune-Checkpoint Inhibitors Dmitrii Shek 1,2, Scott A. Read 1,2,3,5, Adnan Nagrial 3,4,5, Matteo S. Carlino 3,4,5,6, Jacob George 2,4,5, Bo Gao 3,4 & Golo Ahlenstiel 1,2,3,4,5 1 – Blacktown Clinical School and Research Centre, Western Sydney University, Blacktown, NSW, Australia 2 – Storr Liver Centre, Westmead Institute for Medical Research, Westmead, NSW, Australia 3 – Blacktown Hospital, Blacktown, NSW, Australia 4 – Westmead Hospital, Westmead, NSW, Australia 5 – Westmead Clinical School, the University of Sydney, NSW, Australia 6 – Melanoma Institute Australia, Wollstonecraft, NSW, Australia Introduction. Immune-checkpoint inhibitors (ICIs) are monoclonal antibodies (mAbs) that neutralise inhibitory CTLA-4 and PD-1 signalling pathways and boost cytotoxic T cell antitumor activity. ICIs have been proven effective in various malignancies, but there is a lack of knowledge regarding factors associated with ICI efficacy and safety. Non-coding RNAs (ncRNAs) are abundant (up to 70% of the human genome) regulators of gene expression, with proven abilities to promote cancer drug resistance. This study aimed to examine the expression of ncRNA genes among cancer patients treated with ICIs, with respect to treatment response. Methods. Gene expression data was downloaded from the NCBI GEO database. Effect-size (standardized mean difference [SMD]) was calculated using Hedges’ g method and further meta-analysis was conducted in Stata v16 software. DAVID online bioinformatics tool was used to elaborate mechanisms of established genes Results. We identified two datasets derived from patients undergoing anti-PD-1 mAb (nivolumab) therapy: GSE79691 (metastatic melanoma [MM]) and GSE67501 (renal cell carcinoma [RCC]). Both studies evaluated RNA from Formalin-Fixed Paraffin Embedded (FFPE) specimens. MiR-27B (p=0.02) and miR-let7D (p=0.003) were significantly higher among non-responders to ICI therapy compared to responders in both datasets. In particular, overall SMD was 4.57 (miR-27B) and 3.9 (miR-let7D) higher among non-responders in both studies with low study heterogeneity scores (I2=22.67% and T2=0.36). In comparison, analysis of datasets GSE99898 (MM) and GSE74174 (RCC) using non-ICI treatment approaches (tyrosine kinase inhibitors) found no significant association between treatment response and the aforementioned microRNAs. Conclusions. We have established that miR-27B and miR-let7D are increased among non-responders to ICI therapy supporting their possible predictive role for ICI therapeutic response. Because miR-27B, miR-let7D influence PI3K/Akt and Wnt/β-catenin signalling pathways, further studies are required to validate whether these microRNAs solely modulate cancer progression or are unique to ICI therapy response.

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