Изменения иммунной системы в патогенезе нейрофиброматоза 1-го типа

Нейрофиброматоз 1-го типа (НФ1) – наследственный опухолевый синдром, встречающийся с частотой 1:3000 населения. НФ1 обусловлен герминативными гетерозиготными мутациями в гене NF1, который кодирует онкосупрессор нейрофибромин. Для заболевания характерно прогрессирующее течение с образованием множества нейрофибром, в инициировании и росте которых важную роль играют NF1^+/– -тучные клетки, макрофаги и лимфоциты. Соответственно, дефицит нейрофибромина нарушает дифференцировку и корректное функционирование клеток иммунной системы. Об этом свидетельствуют повышенный риск развития лейкозов у больных НФ1 и роль мутаций NF1 в развитии спорадических гемобластозов. В нейрофибромах NF1^–/– -клетки Шванна стимулируют миграцию мастоцитов, которые активно дегранулируют, способствуя неоангиогенезу, воспалению, пролиферации фибробластов и выработке ими избытка коллагена. В связи с этим в лечении НФ1 рекомендовано применение кетотифена и ингибитора kit/fms-киназы. Макрофаги и Т-лимфоциты в нейрофибромах не обеспечивают противоопухолевого ответа, а способствуют воспалению и росту опухоли. Они продуцируют сигнальный белок STAT3 (передатчик сигнала и активатор транскрипции 3), TGF-β (трансформирующий фактор роста β), EGFR (рецептор эпидермального фактора роста), IL-6, IL-4 (интерлейкины 6 и 4) и PD-1. Поэтому перспективным направлением является терапия НФ1 ингибиторами STAT3 и иммунными чекпойнт-ингибиторами, блокирующими лиганд программируемой клеточной гибели 1 (PD-L1). Активация сигнальных путей MEK при НФ1 приводит к стимуляции PD-L1, поэтому эффективными в лечении НФ1 оказались ингибиторы MEK, которые подавляют также систему RAS/RAF/MEK/ERK. Поскольку соматические мутации в гене NF1 играют роль в развитии спорадических злокачественных неоплазм, для их лечения могут быть использованы разрабатываемые методы терапии НФ1.

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