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The interplay between the vaginal microbiome and innate immunity in the focus of predictive, preventive, and personalized medical approach to combat HPV-induced cervical cancer

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Abstract

HPVs representing the most common sexually transmitted disease are a group of carcinogenic viruses with different oncogenic potential. The immune system and the vaginal microbiome represent the modifiable and important risk factors in HPV-induced carcinogenesis. HPV infection significantly increases vaginal microbiome diversity, leading to gradual increases in the abundance of anaerobic bacteria and consequently the severity of cervical dysplasia. Delineation of the exact composition of the vaginal microbiome and immune environment before HPV acquisition, during persistent/progressive infections and after clearance, provides insights into the complex mechanisms of cervical carcinogenesis. It gives hints regarding the prediction of malignant potential. Relative high HPV prevalence in the general population is a challenge for modern and personalized diagnostics and therapeutic guidelines. Identifying the dominant microbial biomarkers of high-grade and low-grade dysplasia could help us to triage the patients with marked chances of lesion regression or progression. Any unnecessary surgical treatment of cervical dysplasia could negatively affect obstetrical outcomes and sexual life. Therefore, understanding the effect and role of microbiome-based therapies is a breaking point in the conservative management of HPV-associated precanceroses. The detailed evaluation of HPV capabilities to evade immune mechanisms from various biofluids (vaginal swabs, cervicovaginal lavage/secretions, or blood) could promote the identification of new immunological targets for novel individualized diagnostics and therapy. Qualitative and quantitative assessment of local immune and microbial environment and associated risk factors constitutes the critical background for preventive, predictive, and personalized medicine that is essential for improving state-of-the-art medical care in patients with cervical precanceroses and cervical cancer. The review article focuses on the influence and potential diagnostic and therapeutic applications of the local innate immune system and the microbial markers in HPV-related cancers in the context of 3P medicine.

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Funding

Open Access funding was enabled and organized by Projekt DEAL. This work was supported by the Grant Agency of the Ministry of Education of the Slovak Republic under contract no. 1/0124/17, the Slovak Research and Development Agency under contract no. APVV-16–0021, the Ministry of Health grant no. 2018/20-UKMT-16, and also by the project molecular diagnosis of cervical cancer, ITMS: 26220220113 supported by the Operational Programme Research and Innovation funded by the ERDF. D.B. was supported by a National Priorities Research Program grant (NPRP 11S-1214–170101) from the Qatar National Research Fund (QNRF, a member of Qatar Foundation).

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  1. Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 036 01, Martin, Slovakia

    Erik Kudela, Alena Liskova, Marek Samec, Lenka Koklesova, Tomas Rokos, Erik Kozubik, Terezia Pribulova & Kamil Biringer

  2. Jessenius Faculty of Medicine, Biomedical Centre Martin, Comenius University in Bratislava, 03601, Martin, Slovakia

    Veronika Holubekova

  3. Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar

    Kevin Zhai & Dietrich Busselberg

  4. Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia

    Peter Kubatka

  5. European Association for Predictive, Preventive and Personalised Medicine, EPMA, 1160, Brussels, Belgium

    Peter Kubatka

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  1. Erik Kudela
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Contributions

E.K. was responsible for the paper concepts, draft, and PPPM-related contents. The manuscript was drafted by E.K., A.L., M.S., L.K., V.H., T.R, E.K., and T.P.

D.B., K.Z., P.K., and K.B. critically revised the manuscript. The tables were created by A.L., M.S., and L.K. Figures were prepared by M.S. and E.K.

P.K., D.B., and K.B. provided a skilled assistance and supervised the overall preparation of the manuscript. K.Z. and D.B. were responsible for English corrections.

All authors have read and agreed to the published version of the manuscript.

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Correspondence to Kamil Biringer.

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Kudela, E., Liskova, A., Samec, M. et al. The interplay between the vaginal microbiome and innate immunity in the focus of predictive, preventive, and personalized medical approach to combat HPV-induced cervical cancer. EPMA Journal 12, 199–220 (2021). https://doi.org/10.1007/s13167-021-00244-3

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