mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-SIC-2965mimmun-2965Research ArticleОБЗОРЫREVIEWSРастворимые молекулы иммунных контрольных точек: механизмы образования, функции, роль при злокачественных новообразованияхSoluble immune checkpoint molecules: mechanism of formation, function, role in malignant neoplasmshttps://orcid.org/0000-0002-1022-8127ГлазановаТ. В.GlazanovaT. V.

Глазанова Татьяна Валентиновна - д.м.н., главный научный сотрудник научно-исследовательской лаборатории иммунологии

191024, Санкт-Петербург, ул. 2-я Советская, 16

Тел.: 8 (812) 309-79-81

Tatiana V. Glazanova, PhD, MD (Medicine), Chief Research Associate, Laboratory of Immunology

16 2nd Sovetskaya St St. Petersburg 191024

Phone: +7 (812) 309-79-81

tatyana-glazanova@yandex.ruhttps://orcid.org/0000-0001-7756-4902ПавловаИ. Е.PavlovaI. E.

Павлова И.Е. – д.м.н., главный научный сотрудник научно-исследовательской лаборатории иммунологии

Санкт-Петербург

Pavlova I.E., PhD, MD (Medicine), Chief Research Associate, Laboratory of Immunology

St. Petersburg

pavlova@niigt.ruhttps://orcid.org/0000-0003-0489-1763КузьмичЕ. В.KuzmichE. V.

Кузьмич Е.В. – к.м.н., ведущий научный сотрудник научно-исследовательской лаборатории иммунологии

Санкт-Петербург

Kuzmich E.V., PhD (Medicine), Leading Research Associate, Laboratory of Immunology

St. Petersburg

yelenakuzmich@gmail.comhttps://orcid.org/0000-0002-6690-3742БубноваЛ. Н.BubnovaL. N.

Бубнова Л.Н. – д.м.н., профессор, заслуженный деятель науки РФ, главный  научный сотрудник научно-исследовательской лаборатории иммунологии; профессор кафедры иммунологии

Санкт-Петербург

Bubnova L.N., PhD, MD (Medicine), Professor, Honored Scientist of the Russian Federation, Chief Research Associate, Laboratory of Immunology; Professor, Department of Immunology

 

St. Petersburg

lnbubnova@mail.ruФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства»РоссияRussian Research Institute of Haematology and Transfusiology, Federal Medical and Biological AgencyRussian FederationФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства»; ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФРоссияRussian Research Institute of Haematology and Transfusiology, Federal Medical and Biological Agency; First St. Petersburg State I. Pavlov Medical UniversityRussian Federation2025080120252712134Copyright © Глазанова Т.В., Павлова И.Е., Кузьмич Е.В., Бубнова Л.Н., 20252025Глазанова Т.В., Павлова И.Е., Кузьмич Е.В., Бубнова Л.Н.Glazanova T.V., Pavlova I.E., Kuzmich E.V., Bubnova L.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/2965

Иммунные контрольные точки (ИКТ) – это обширный комплекс стимулирующих и ингибирующих сигнальных путей, играющих важную роль в точной регулировке иммунных реакций. Традиционно ИКТ считались исключительно связанными с клеточной мембраной системами рецепторов и лигандов, способными запускать или блокировать функционирование иммунных клеток, однако за последнее десятилетие доказано их существование в виде растворимых форм (растворимые молекулы иммунных контрольных точек, или sИКТ). sИКТ – биологически активные регуляторы, участвующие в паракринной и системной модуляции иммунных реакций, подобно цитокинам. В периферической крови здоровых людей присутствуют sИКТ, обладающие свойствами как стимуляторов, так и ингибиторов иммунной системы, и их баланс может нарушаться при многих онкологических заболеваниях, COVID-19, ВИЧ-инфекции. Имеется много данных о связи наличия sИКТ с различными заболеваниями, однако ряд ключевых аспектов их биологии до конца не уточнен. Наиболее широко изучаемыми являются молекулы PD-1 (programmed death receptor-1) и его лиганды PD-L1 и PD-L2, а также CTLA-4 (cytotoxic T lymphocyte antigen-4), TIM-3 (T cell immunoglobulin and mucin-domain containing-3), VISTA (V-domain Ig-containing suppressor of T cell activation). Механизмы образования растворимых форм сложны и разнообразны и включают альтернативный сплайсинг, отщепление мембранных эктодоменов, протеолитическое расщепление. Среди молекулярных механизмов, лежащих в основе синтеза и высвобождения sPD-1 и sPD-L1, наиболее важными являются альтернативный сплайсинг мРНК и трансляция изоформ, лишенных трансмембранных доменов, а образование растворимой формы TIM-3 происходит путем разрезания внеклеточных участков трансмембранных белков посредством протеазы ADAM10. В обзорной статье приведены данные об основных sИКТ, включая sPD-1, sPD-L1, экзосомальный sPD-L1, sCTLA-4 и ряд других. Описаны молекулярные механизмы их образования, биологические функции в поддержании иммунного гомеостаза, а также прогностическое значение изменения их содержания у больных злокачественными новообразованиями (включая немелкоклеточный рак легкого, гепатоцеллюлярный рак, рак молочной железы, рак почки, рак кожи, рак желудка и ряд других), а также при злокачественных заболеваниях системы крови (включая лимфомы, хронический лимфолейкоз, острый миелобластный лейкоз, множественную миелому).

Immune checkpoints (ICs) represent a broad set of stimulatory and inhibitory signaling pathways playing an important role in regulation of immune responses. Initially, ICs have been considered solely as cell membrane-bound receptor and ligand systems, triggering or blocking immune cell function. Over the past decade they have been proven to exist in soluble forms (sICs). sICs are biologically active regulators involved in paracrine and systemic modulation of immune responses, similar to cytokines. Normally, sICs exert both stimulatory and inhibitory effects on the immune system, and their balance may be disturbed in many malignant neoplasms, COVID-19, HIV infection. There is a lot of data on the connection between sICs and various diseases, but a number of key aspects of their biology have not been fully clarified. The most widely studied are PD-1 (programmed death receptor-1) and its ligands PD-L1 and PD-L2, CTLA-4 (cytotoxic T lymphocyte antigen-4), TIM-3 (T cell immunoglobulin and mucin-domain containing-3), VISTA (V-domain Ig-containing suppressor of T cell activation). The mechanisms of soluble form formation are complex and diverse and include alternative splicing, cleavage of membrane ectodomains, and proteolytic cleavage. The most important molecular mechanisms underlying the synthesis and release of sPD-1 and sPD-L1 are alternative splicing of mRNA and translation of isoforms lacking transmembrane domains, while the formation of sTIM-3 occurs by cleaving the extracellular regions of transmembrane proteins by protease ADAM10. The review article provides data on the main sICs, including sPD-1, sPD-L1, exosomal sPD-L1, sCTLA-4, and several others. The molecular mechanisms of their formation, biological functions in maintaining immune homeostasis, prognostic significance of changes in their content are described in patients with solid malignant tumors (nonsmall cell lung cancer, hepatocellular cancer, breast cancer, kidney cancer, skin cancer, gastric cancer, etc.), as well as for hematologic malignancies (lymphoma, chronic lymphocytic leukemia, acute myeloblastic leukemia, multiple myeloma).

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The authors declare that there are no conflicts of interest present.