EXOSOMAL MIRNAS AS POSSIBLE PREDICTORS OF IMMUNE CHECKPOINT INHIBITORS THERAPY RESPONSE IN CLEAR CELL RENAL CELL CARCINOMA

DOI: https://doi.org/10.29296/24999490-2023-04-06

I.R. Gilyazova(1–3), D.D. Asadullina(1, 2), E.A. Ivanova(1), A.A. Izmailov(4), D.A. Kudlay(5, 6), G.R. Gilyazova(2), E.F. Galimova(2),
I.B. Ermakov(4), R.R. Rakhimov(4), E.V. Popova4, A.F. Nasretdinov(4), A.B. Sultanbaev(4), E.K. Khusnutdinova(1), V.N. Pavlov(2)
1-Institute of Biochemistry and Genetics, Ufa Scientific Center, RAS, Oktyabrya Ave., 71, Ufa, 450054, Russian Federation;
2-Bashkir State Medical University, Lenin Str., 3, Ufa, 450008, Russian Federation;
3-«Saint Petersburg State University» (Department of Biology), Universitetskaya Emb., 7–9, St. Petersburg, 199034, Russian Federation;
4-Republican Clinical Oncology Dispensary, Oktyabrya Ave., 73/1, Ufa, 450054, Russian Federation;
5-I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University),
Trubetskaya Str., 8, p. 2, Moscow, 119991, Russian Federation;
6-State Research Centre Institute of Immunology FMBA of Russia, Kashirskoe Hw, 24, Moscow, 115522, Russian Federation

Despite significant advance in clear cell renal cell carcinoma treatment, immune checkpoint inhibitors (ICIs) still have limited therapeutic efficacy. Taking into account the resistance to immunotherapy, observed in malignant neoplasms, the search for predictive markers of response to ICI therapy in patients with clear cell renal cell carcinoma (ccRCC) is under active investigation. Recent scientific studies demonstrate that exosomal miRNAs are key modulators of tumor signaling and determinants of the tumor microenvironment. Dysregulation of miRNAs can affect the immunogenicity of ccRCCs and response to ICI therapy, making them attractive as predictive molecular genetic biomarkers and targets for potential therapeutic developments. The aim of the study was to evaluate the expression levels of exosomal miRNAs-424,-503,-885,-149 in ccRCC patients who received ICI therapy. Material and methods: The study included 42 patients from whom venous blood samples were taken before and after ICI therapy. Expression analysis was performed by quantitative real-time PCR. Results: For miRNA-424 statistically significant differences in expression levels in the comparison groups were demonstrated. It was shown that the expression level of microRNA-424 increased after therapy (M±SM 1.202±0.15) compared with the expression level before treatment with nivolumab (M±SM 0.63±0.17; p-value=0.03). Despite the fact that miRNA-424 and miRNA-503 are clustered, miRNA-503, like other examined miRNAs, did not show any differences in expression levels between the compared groups. Conclusion: miRNA-424 can be used to create a panel of molecular markers within other previously discovered markers to assess the effectiveness of ICI therapy. Despite the fact that this study is pilot and requires validation on larger samples, it confirms the possibility of using miRNAs as additional prognostic markers for ICI therapy.
Keywords: 
renal cell carcinoma; ICI therapy; exosomal miRNAs; immune-related adverse events; PD-1/PD-L1; biomarkers
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