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Published on: May 27, 2016
Exosomal miRNA-146a is downregulated in clear cell renal cell carcinoma patients with severe immune-related adverse
E Ivanova1,2, D Asadullina1, R Rakhimov3
1Institute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, 450054, Russian Federation.
Abstract:
Here we report the results of the pilot project of exosomal miRNA expression levels in clear cell renal cell carcinoma (ccRCC) patients with different clinical response to ICIs (nivolumab) and treatment related toxicity. Immune-related adverse events (irAEs) are a major cause of immune checkpoint inhibitors cancellation and therapy failure. Modern studies demonstrate evidence that exosomes are of great importance in the formation of tumor resistance to ICIs drugs and therapy. We performed exosomal miRNA-146a expression analysis using qPCR on 86 ccRCC patients and revealed a statistically significant (p = 0.01) decreased expression level in ccRCC patients with CTCAE grade 3-4 (M±SEM 1.71 ± 0.13) compared to CTCAE grade 0-2 group (M±SEM 2.30 ± 0.24). The expression levels of miRNA-126, miRNA-218 and miRNA-410 did not show statistically significant differences in the comparison groups (p > 0.05). Association analysis of rs2910164 in the miRNA-146a gene demonstrated that CC genotype and C allele carriers had higher risk of developing severe irAEs (p = 0.03, OR = 6.12; p = 0.01, OR = 2.42, respectively) compare with GG and GC carriers. That is the first attempt to identify biomarkers of ICIs treatment efficacy for ccRCC in the Volga-Ural region based on exosomal miRNAs analysis.
Insights
Exosomal microRNA-146a levels may predict immune-related adverse events in clear cell renal cell carcinoma patients treated with immune checkpoint inhibitors (ICIs). Lower miRNA-146a expression correlates with severe toxicity, suggesting its potential as a biomarker for ICI therapy response.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
- Genetics
Background:
- Immune checkpoint inhibitors (ICIs) are crucial for cancer therapy but can cause immune-related adverse events (irAEs).
- Exosomes play a role in tumor resistance to ICIs, highlighting the need for predictive biomarkers.
- Clear cell renal cell carcinoma (ccRCC) treatment efficacy and toxicity can vary significantly among patients.
Purpose of the Study:
- To investigate exosomal microRNA (miRNA) expression levels in ccRCC patients undergoing ICI therapy.
- To identify potential biomarkers for predicting clinical response and treatment-related toxicity to ICIs.
- To explore the association between specific miRNA genetic variations and the risk of severe irAEs.
Main Methods:
- Exosomal miRNA expression analysis (miRNA-146a, -126, -218, -410) using quantitative polymerase chain reaction (qPCR).
- Analysis of 86 ccRCC patients with varying clinical responses and toxicity levels to nivolumab.
- Genotyping of the rs2910164 polymorphism in the miRNA-146a gene.
Main Results:
- Significantly decreased exosomal miRNA-146a expression was observed in ccRCC patients with severe irAEs (CTCAE grade 3-4) compared to those with mild irAEs (grade 0-2).
- No significant differences in expression levels were found for miRNA-126, miRNA-218, and miRNA-410.
- Carriers of the CC genotype and C allele in rs2910164 of miRNA-146a had a higher risk of developing severe irAEs.
Conclusions:
- Exosomal miRNA-146a expression may serve as a predictive biomarker for ICI-induced toxicity in ccRCC patients.
- The rs2910164 polymorphism in miRNA-146a is associated with an increased risk of severe irAEs.
- This study represents a novel attempt to identify exosomal miRNA biomarkers for ICI efficacy in ccRCC within the Volga-Ural region.
