Exosomal miRNA-146a and miRNA-424 as possible predictors of immune checkpoint inhibitors therapy response in clear cell renal cell carcinoma

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Abstract

Clear cell renal cell carcinoma (ccRCC) is a malignant kidney tumor with a poor prognosis and difficult to treat. Despite significant advances in the treatment of ccRCC, immune checkpoint in-hibitors (ICI) still have limited therapeutic efficacy. A growing body of work has demonstrated that exosomal microRNAs are key modulators of tumor signaling and determinants of the tumor microenvironment. Disruption of microRNA regulation may affect ccRCC immunogenicity and response to ICI therapy, making them attractive for use as prognostic molecular genetic bi-omarkers. We evaluated exosomal miRNAs (miRNA-424,-146a,-503, -144) expression levels before and after ICI therapy in plasma samples obtained from 42 ccRCC patients. Expression analysis was performed by real-time PCR method. The results showed that the expression levels of miRNA-424 and miRNA-146a were upregulated after ICI therapy treatment (miRNA-424 = Mean ± SEM 1.202 ± 0.15 and miRNA-146a = 12.22 ± 1.45) compared expression levels before therapy (miRNA-424=Mean±SEM 0.63 ± 0.17; p-value = 0.03 and miRNA-146a = 7.03 ± 0.90; p-value = 0.006). miRNA-424 and miRNA-146a can be used to create a panel of molecular markers for evaluating the effectiveness of immune checkpoint inhibitors therapy. Even though this is very preliminary and requires further studying on a larger sample, it further increases the interest in using microRNAs, as additional ICI therapeutic markers capable of modulating immune tolerance.

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About the authors

D. D. Asadullina

Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences; Federal State Budgetary Educational Institution of Higher Education “Bashkir State Medical University” of the Ministry of Health of the Russian Federation

Author for correspondence.
Email: dilara.asadullina@yandex.ru
Russian Federation, Ufa, 450054; Ufa, 450008

I. R. Gilyazova

Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences; Federal State Budgetary Educational Institution of Higher Education “Bashkir State Medical University” of the Ministry of Health of the Russian Federation

Email: gilyasova_irina@mail.ru
Russian Federation, Ufa, 450054; Ufa, 450008

E. A. Ivanova

Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences

Email: dilara.asadullina@yandex.ru
Russian Federation, Ufa, 450054

S. M. Izmailova

Federal State Budgetary Educational Institution of Higher Education “Bashkir State Medical University” of the Ministry of Health of the Russian Federation

Email: dilara.asadullina@yandex.ru
Russian Federation, Ufa, 450008

G. R. Gilyazova

Federal State Budgetary Educational Institution of Higher Education “Bashkir State Medical University” of the Ministry of Health of the Russian Federation

Email: dilara.asadullina@yandex.ru
Russian Federation, Ufa, 450008

V. N. Pavlov

Federal State Budgetary Educational Institution of Higher Education “Bashkir State Medical University” of the Ministry of Health of the Russian Federation

Email: dilara.asadullina@yandex.ru
Russian Federation, Ufa, 450008

E. K. Khusnutdinova

Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences; Federal State Budgetary Educational Institution of Higher Education “Bashkir State Medical University” of the Ministry of Health of the Russian Federation

Email: dilara.asadullina@yandex.ru
Russian Federation, Ufa, 450054; Ufa, 450008

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2. Fig. 1. Expression levels of exosomal microRNAs in patients with scPCC treated with ICTI. a – miRNA-424; b – miRNA-503; c – miRNA-146a; d – miRNA-144. The significance level of the p-value was calculated using the Wilcoxon criterion. bt – before therapy; at – after therapy.

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3. Fig. 2. GO signaling pathway enrichment analysis and a diagram reflecting the results of the KEGG pathway enrichment analysis performed for microRNA-146a and microRNA-424 and their validated targets.

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4. Fig. 3. Signaling pathway of PD-L1 expression and PD-1 control points, including validated target genes microRNA-146a and microRNA-424 (highlighted in red), according to the KEGG database.

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5. Fig. 4. ROC analysis for predicting the response to ICTI therapy in scPCC based on the analysis of the expression of exosomal microRNA-424.

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