Exosomal mirnas as possible predictors of immune checkpoint inhibitors therapy response in clear cell renal cell carcinoma

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Abstract

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.

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About the authors

Irina R. Gilyazova

Institute of Biochemistry and Genetics, Ufa Scientific Center, RAS; Bashkir State Medical University; «Saint Petersburg State University» (Department of Biology)

Email: gilyasova_irina@mail.ru
ORCID iD: 0000-0001-9499-5632

Senior Researcher at the Institute of Biochemistry and Genetics of the Ufa Scientific Center of the Russian Academy of Sciences; Head of the Laboratory of Molecular Genetics of the Institute of Urology and Clinical Oncology of the Bashkir State Medical University of the Ministry of Health of the Russian Federation, Associate Professor of the Department of Medical Genetics and Fundamental Medicine of Bashkir State Medical University, senior Researcher, St. Petersburg State University (Faculty of Biology), candidate of Biological Sciences, associate Professor

Russian Federation, Oktyabrya Ave., 71, Ufa, 450054; Lenin Str., 3, Ufa, 450008; Universitetskaya Emb., 7–9, St. Petersburg, 199034

Dilara D. Asadullina

Institute of Biochemistry and Genetics, Ufa Scientific Center, RAS; Bashkir State Medical University

Email: dilara.asadullina@yandex.ru
ORCID iD: 0000-0003-4911-8037

postgraduate student in the scientific specialty 1.5.7 – Genetics, Institute of Biochemistry and Genetics of the Ufa Scientific Center of the Russian Academy of Sciences, Junior Researcher of Molecular Genetics at the Institute of Urology and Clinical Oncology of the Bashkir State Medical University of the Ministry of Health of the Russian Federation

Russian Federation, Oktyabrya Ave., 71, Ufa, 450054; Lenin Str., 3, Ufa, 450008

Elizaveta A. Ivanova

Institute of Biochemistry and Genetics, Ufa Scientific Center, RAS

Email: lissa987@yandex.ru
ORCID iD: 0000-0002-7853-8658

Researcher at the Institute of Biochemistry and Genetics of the Ufa Scientific Center of the Russian Academy of Sciences, candidate of Biological Sciences

Russian Federation, Oktyabrya Ave., 71, Ufa, 450054

Adel A. Izmailov

Republican Clinical Oncology Dispensary

Email: izmailov75@mail.ru
ORCID iD: 0000-0002-8461-9243

Chief Physician of the Republican Clinical Oncology Dispensary, doctor of Medical Sciences, Associate Professor

Russian Federation, Oktyabrya Ave., 73/1, Ufa, 450054

Dmitry A. Kudlay

I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University); State Research Centre Institute of Immunology FMBA of Russia

Email: D624254@gmail.com
ORCID iD: 0000-0003-1878-4467

Professor of the Department of Pharmacology of the Institute of Pharmacy of the I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Leading Researcher at the Laboratory of Personalized Medicine and Molecular Immunology No. 71 of the Federal State Budgetary Institution “SSC Institute of Immunology” of the FMBA of Russia, doctor of Medical Sciences, Professor, Corresponding Member

Russian Federation, Trubetskaya Str., 8, p. 2, Moscow, 119991; Kashirskoe Hw, 24, Moscow, 115522

Gulshat R. Gilyazova

Bashkir State Medical University

Email: gulshatik2001@mail.ru
ORCID iD: 0000-0001-7189-5532

student of Bashkir State Medical University

Russian Federation, Lenin Str., 3, Ufa, 450008

Elmira F. Galimova

Bashkir State Medical University

Email: efgalimova@mail.ru
ORCID iD: 0000-0002-3351-7669

Professor of the Department of Pathological Physiology of the BSMU of the Ministry of Health of the Russian Federation, doctor of Medical Sciences, Professor

Russian Federation, Lenin Str., 3, Ufa, 450008

Igor B. Ermakov

Republican Clinical Oncology Dispensary

Email: ermakoff79@mail.ru
ORCID iD: 0009-0002-6170-3423

Head of the Department of the Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Belarus

Russian Federation, Oktyabrya Ave., 73/1, Ufa, 450054

Radmir R. Rakhimov

Republican Clinical Oncology Dispensary

Email: radmir-rr@mail.ru
ORCID iD: 0000-0002-2488-597X

Oncologist at the Republican Clinical Oncology Dispensary, Candidate of Medical Sciences

Russian Federation, Oktyabrya Ave., 73/1, Ufa, 450054

Ekaterina V. Popova

Republican Clinical Oncology Dispensary

Email: katusha-pv@mail.ru
ORCID iD: 0000-0003-1242-759X

Head of the Department of the Republican Clinical Oncology Dispensary of the Russian Federation

Russian Federation, Oktyabrya Ave., 73/1, Ufa, 450054

Ainur F. Nasretdinov

Republican Clinical Oncology Dispensary

Email: rkodrb@yandex.ru
ORCID iD: 0000-0001-8340-7962

Head of the department of the Republican Clinical Oncology Dispensary of the Russian Federation

Russian Federation, Oktyabrya Ave., 73/1, Ufa, 450054

Alexander V. Sultanbaev

Republican Clinical Oncology Dispensary

Email: rkodrb@yandex.ru
ORCID iD: 0000-0003-0996-5995

Head of the department of the Republican Clinical Oncology Dispensary of the Russian Federation, сandidate of Medical Sciences

Russian Federation, Oktyabrya Ave., 73/1, Ufa, 450054

Elza K. Khusnutdinova

Institute of Biochemistry and Genetics, Ufa Scientific Center, RAS, Bashkir State Medical University

Author for correspondence.
Email: molgen@anrb.ru
ORCID iD: 0000-0003-2987-3334

Director of the Institute of Biochemistry and Genetics of the Ufa Scientific Center of the Russian Academy of Sciences. Doctor of Biological Sciences, Professor

Russian Federation, Oktyabrya Ave., 71, Ufa, 450054; Lenin Str., 3, Ufa, 450008

Valentin N. Pavlov

Bashkir State Medical University

Email: vpavlov3@yandex.ru
ORCID iD: 0000-0003-2125-4897

Rector of Bashkir State Medical University. Doctor of Medical Sciences, Professor

Russian Federation, Lenin Str., 3, Ufa, 450008

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2. Fig. 1. Exosomal microRNA expression levels in patients with ccRCC treated with nivolumab: а – microRNA-424; b – microRNA-503; c – microRNA-149; d – microRNA-885. Level of significance (p-value) calculated using Wilcoxon criterion. Bt – before therapy; at – after therapy

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3. Fig. 2. MicroRNA-424 targeting genes and the role of microRNA-424 in oncogenesis (by Xuan J,2022 with changes [22])

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