Механизмы цитотоксичности пассивной анти-GD2-иммунотерапии при опухолях детского возраста

Клетки нейробластомы, сарком мягких тканей, остеосаркомы, саркомы Юинга и некоторых других опухолей у детей и взрослых способны экспрессировать дисиалоганглизид GD2. Включение в протоколы терапии нейробластомы анти-GD2-моноклональных антител позволило улучшить результаты лечения. проводятся исследования эффективности использования этих моноклональных антител и при других опухолях.

В данном обзоре описаны основные клеточные и молекулярные процессы, происходящие при пассивной анти-GD2 иммунотерапии при опухолях детского возраста, а также факторы, способные повлиять на них. Мы пришли к выводу, что ведущую роль в развитии цитотоксичности играет антителозависимая клеточная цитотоксичность, реализуемая естественными киллерами по классическому механизму с индукцией каспазазависимого апоптоза, а также макрофагами и нейтрофилами посредством фагоцитоза, трогоцитоза и прямой цитотоксичности. Эффективному фагоцитозу способствует экспрессия кальретикулина опухолевыми клетками и рецептора LRP1 фагоцитами, а уклонению от фагоцитоза – экспрессия опухолевыми клетками CD47 и его взаимодействие с SIRPα на фагоцитах. параллельно происходит активация Т-клеточного адаптивного иммунного ответа. использование гранулоцитарного и гранулоцитарно-макрофагального колониестимулирующих факторов может усиливать цитотоксичность. Добавление экзогенного интерлейкина 2 не повышает эффективность лечения, а применение интерлейкинов 15 и 21 усиливает цитотоксичность in vitro, что требует проведения клинических исследований. комплементзависимая цитотоксичность, вероятно, не оказывает влияния на терапевтическую эффективность пассивной анти-GD2-иммунотерапии. Опухолевое микроокружение и молекулярные особенности иммунокомпетентных клеток могут влиять на анти-GD2 опосредованную цитотоксичность, особенно при совместном использовании анти-GD2 моноклональных антител и ингибиторов рецептора программируемой клеточной гибели 1 (PD-1). Таким образом, дальнейшее изучение данного вопроса особенно актуально. Анти-GD2-моноклональные антитела могут снижать пролиферативную активность и индуцировать апоптоз опухолевых клеток путем ингибирования сигнальных путей (главным образом PI3K/Akt/mTOR), транскрипционных факторов, комплексов фокальной адгезии и интегринов. Вероятны и механизмы индукции митохондриальнозависимой клеточной гибели, имеющей признаки апоптоза и некроза.

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