Механизмы резистентности к иммунотерапии при MSI фенотипе
https://doi.org/10.18027/2224-5057-2025-15-3s1-11-30
Аннотация
Цель: Обобщить современные представления о механизмах первичной и приобретённой резистентности к ингибиторам контрольных точек (ИКТ) при колоректальном раке (КРР) с dMMR / MSI.
Материалы и методы: Нарративный обзор рецензируемой литературы и результатов клинических исследований ИКТ, включающий молекулярно-генетические, иммунологические, морфологические и микробиотические маркеры резистентности.
Результаты: Резистентность при КРР с dMMR / MSI имеет многофакторную природу, к которой можно отнести дефекты антигенной презентации (β2‑микроглобулин, компоненты APM, HLA), нарушения сигнального пути IFN-γ / JAKSTAT, гиперактивность WNT / β-катенина, TGF-β-опосредованный сигналинг и ремоделирование стромы, а также особенности транскриптомных подтипов. Вклад микроокружения включает накопление Treg, MDSC, нейтрофилов и М2‑макрофагов, активацию фибробластов, ангиогенез и особенности метаболизма опухолевых клеток, а также экспансию дополнительных иммунных контрольных точек (LAG-3, TIM-3, TIGIT, IDO1), снижающих эффективность PD-1‑блокады. На уровне биомаркеров значимы: вариабельность TMB и степень выраженности MSI, результаты Immunoscore, морфологические признаки (например, наличие муцинозного компонента в опухоли), а также генетических причин развития MSI. Микробиота (в том числе F. nucleatum) ассоциирована с особенностями микрокружения опухоли и чувствительностью к ИКТ. Перспективные пути преодоления резистентности включают ко-блокаду PD-1 с CTLA-4 или LAG-3, сочетание с анти-VEGF-терапией и ингибиторами TGF-β, воздействие на миелоидные клетки, модуляцию микробиоты и новые таргетные подходы (например, ингибирование WRN).
Заключение: Несмотря на высокую иммуногенность MSI-ассоциированного КРР, резистентность остаётся существенной клинической проблемой и требует стратификации по совокупности геномных, транскриптомных и иммунных признаков. Наиболее перспективной видится персонализированная комбинационная иммунотерапия на основе интегральной оценки антигенпрезентирующей функции, интерферонового сигналинга, микроокружения, морфологии, микробиоты и клинических признаков.
Ключевые слова
MSI,
dMMR,
колоректальный рак,
иммунотерапия,
ингибиторы контрольных точек,
резистентность,
микроокружение опухоли
Об авторе
М. Ю. Федянин
ФГБУ «Научный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России;
ФГБУ «Национальный медико-хирургический Центр им. Н. И. Пирогова» Минздрава России;
ГБУЗ «Московский многопрофильный клинический центр «Коммунарка» Департамента здравоохранения г. Москвы»
Россия
Конфликт интересов:
Россия
Михаил Юрьевич Федянин
115478 Москва, Каширское шоссе, 23
105203 Москва, ул. Нижняя Первомайская, 70
108814, Москва, п. Коммунарка, ул. Сосенский стан, 8
Конфликт интересов:
Автор заявляет об отсутствии возможных конфликтов интересов.
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Федянин М.Ю. Механизмы резистентности к иммунотерапии при MSI фенотипе. Malignant tumours. 2025;15(3s1):11-30. https://doi.org/10.18027/2224-5057-2025-15-3s1-11-30
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