Растворимые молекулы иммунных контрольных точек: механизмы образования, функции, роль при злокачественных новообразованиях

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).

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