Cancer UrologyCancer UrologyОнкоурология1726-97761996-1812Publishing House ABV Press165210.17650/1726-9776-2023-19-4-158-166REVIEWSОБЗОРЫFuture of epigenetic immunotherapy in kidney cancerПерспективы эпигенетической иммунотерапии рака почкиhttps://orcid.org/0000-0002-4091-382X4810-2534MustafinR. N.МустафинР. Н.
Russian Federation

Rustam N. Mustafin 

3 Lenina St., Ufa 450008

Мустафин Рустам Наилевич, доцент кафедры медицинской генетики и фундаментальной медицины, кандидат биологических наук

450008 Уфа, ул. Ленина, 3

ruji79@mail.ruBashkir State Medical University, Ministry of Health of RussiaФГБОУ ВО «Башкирский государственный медицинский университет» Минздрава России2912202319415816602012023151120232023https://oncourology.abvpress.ru/oncur/article/view/1652

In clinical practice, immune checkpoint inhibition based on the use of antibodies against PD-1 (programmed death 1), PD-L1 (programmed death-ligand 1) and CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) is actively used for treatment of kidney cancer. However, objective response to monotherapy with these drugs is observed only in 9–24 % of patients, and combinations with other anticancer drugs in most cases cause severe adverse reactions. At the same time, there is an increased risk of toxic liver damage, immune-dependent pneumonitis, and rash. Therefore, it is necessary to search for new methods of immunotherapy, the most promising of which is the method of viral mimicry based on epigenetic stimulation of retroelement expression. Double-stranded retroelement transcripts activate antiviral interferon response that induces apoptosis of tumor cells. To achieve this, inhibitors of DNA methyltransferase, deacetylase and histone methyltransferase are used which have been successfully applied to treat various malignant neoplasms. In the experiment, DNA methyltransferase inhibitor 5-aza-2-deoxytidine (decitabine) effectively inhibited clear cell renal cell carcinoma cells proliferation which indicates their potential in treatment of kidney cancer. However, similarly to other neoplasms, activation of retroelements in renal cell carcinoma serves as initiator of the tumor process as it leads to increased expression of oncogenes, inactivation of tumor suppressors, and genomic instability. Therefore, the method of viral mimicry requires a differentiated approach with inhibition of retroelements involved in carcinogenesis and simultaneous stimulation of expression of retrotransposons that are not involved in the mechanisms of tumor development and have immunogenic properties. For this, microRNAs derived from transposons can be used as guides for DNA methyltransferases. An analysis of scientific literature revealed 41 such microRNAs of which decreased expression in kidney cancer was established for miR-95, -887, -652, -585, -511, -502, -495, -493, -487b, -335; increased for miR-1249, -1266, -151a, -211, -2114, -2355, -28, -3144, -340, -342, -374a, -374b, -3934, -421, -545, -576, -582, -584, -616, -769; and specific expression in different tumor subtypes for miR-708, -577, -450b, -326, -3200, -31, -224, -192, -1271. Since activation of retroelements can lead to insertions into new genome loci with formation of new mutations involved in carcinogenesis, a promising direction in integrated immunotherapy of kidney cancer is the use of reverse transcriptase inhibitors.

В клинической практике для лечения рака почки активно применяется ингибирование иммунных контрольных точек, основанное на использовании антител против PD-1 (programmed death 1), PD-L1 (programmed death ligand 1) и CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4). Однако объективный ответ на монотерапию данными препаратами отмечается лишь у 9–24 % пациентов, а комбинация с другими противоопухолевыми лекарствами приводит к тяжелым побочным реакциям в большинстве случаев. Характерен повышенный риск токсического поражения печени, иммунозависимого пневмонита и сыпи. Поэтому необходим поиск новых способов иммунотерапии, наиболее перспективным из которых является метод вирусной мимикрии, основанный на эпигенетической стимуляции экспрессии ретроэлементов. Их двуцепочечные транскрипты активируют противовирусный интерфероновый ответ, вызывающий апоптоз опухолевых клеток. Для этого используют ингибиторы ДНК-метилтрансферазы, деацетилазы и метилтрансферазы гистонов, успешно применяемые для лечения различных злокачественных новообразований. В эксперименте ингибитор ДНК-метилтрансферазы 5-аза-2-дезоксицитидин (децитабин) эффективно ингибировал пролиферацию клеток светлоклеточной почечно-клеточной карциномы, что свидетельствует о его потенциале в лечении рака почки. Однако, подобно другим неоплазмам, активация специфических ретроэлементов, вовлеченных в канцерогенез, при почечно-клеточной карциноме служит инициатором опухолевого процесса, поскольку приводит к усилению экспрессии онкогенов, инактивации супрессоров опухолей и геномной нестабильности. Поэтому в методе вирусной мимикрии необходим дифференцированный подход с ингибированием вовлеченных в канцерогенез ретроэлементов с одновременной стимуляцией экспрессии ретротранспозонов, не вовлеченных в механизмы развития опухоли и обладающих иммуногенными свойствами. Для этого в качестве гидов ДНК-метилтрансфераз могут быть использованы произошедшие от транспозонов микроРНК. Анализ научной литературы позволил выявить 41 такую микроРНК, среди которых определена сниженная экспрессия при раке почки для miR-95, -887, -652, -585, -511, -502, -495, -493, -487b, -335; повышенная – для miR-1249, -1266, -151a, -211, -2114, -2355, -28, -3144, -340, -342, -374a, -374b, -3934, -421, -545, -576, -582, -584, -616, -769; специфичная для определенных подтипов опухоли – для miR-708, -577, -450b, -326, -3200, -31, -224, -192, -1271. Поскольку активация ретроэлементов может привести к инсерциям в новые локусы генома с образованием новых мутаций, вовлеченных в канцерогенез, перспективным направлением комплексной иммунотерапии рака почки является применение ингибиторов обратной транскриптазы.

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