Иммунотропная терапия: блокада CTLA-4/B7- и PD-1/PD-L1-путей в терапии злокачественных новообразований. Часть 1. Иммунологические аспекты

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Аннотация

Сигнальные пути CTLA-4/B7 и PD-1/PD-L1 являются ключевыми при формировании и поддержании периферической иммунологической толерантности. Взаимодействие рецепторов PD-1 и CTLA-4 со своими лигандами запускает каскад реакций, способствующий подавлению активности эффекторных CD4+- и CD8+-Т-лимфоцитов. Однако роль этих сигнальных каскадов в иммунных реакциях достаточно многогранна. Так, на поверхности Т-клеток CTLA-4 конкурирует с CD28 за лиганды и при взаимодействии с молекулами семейства В7 ингибирует передачу сигнала с Т-клеточного рецептора (TCR). В то же время данное взаимодействие способствует выработке противовоспалительных цитокинов IL-10 и TGF-β регуляторными Т-лимфоцитами (Трег). На регуляторных Т-лимфоцитах CTLA-4 после связывания с молекулами семейства В7 (CD80 и CD86) на поверхности антигенпрезентирующей клетки опосредует CTLA-4-зависимый трогоцитоз, вследствие которого снижается экспрессия молекул семейства B7 на антигенпрезентирующие клетки. Это снижает эффективность антигенпрезентирующих клеток в стимуляции клональной экспансии и выживания активированных Т-клеток в лимфоидной ткани. Молекула PD-1, в свою очередь, экспрессируется на широком спектре клеток, включая эффекторные CD4+- и CD8+-Т-лимфоциты. Данная молекула крайне важна для выживания и проявления эффекторных свойств активированных антиген-специфических Т-лимфоцитов в воспаленных периферических тканях. Кроме того, взаимодействие PD-1 с PD-L1 может стимулировать выработку противовоспалительных цитокинов регуляторных Т-лимфоцитов. При онкологических заболеваниях опухолевые клетки могут использовать преимущества периферической толерантности, реализуемой как молекулой CTLA-4, так и молекулой PD-1. Следовательно, блокада этих рецепторов может выступать эффективным терапевтическим подходом в клинической практике при лечении злокачественных новообразований.

Об авторах

Андрей Алексеевич Шукшин

Национальный медицинский исследовательский центр им. В.А. Алмазова

Email: andrei.shukshinf@yandex.ru
ORCID iD: 0009-0009-0830-1733
Россия, Санкт-Петербург

Артем Аркадьевич Рубинштейн

Национальный медицинский исследовательский центр им. В.А. Алмазова

Автор, ответственный за переписку.
Email: arrubin6@mail.ru
ORCID iD: 0000-0002-8493-5211
SPIN-код: 6025-1790
Россия, Санкт-Петербург

Алексей Сергеевич Головкин

Национальный медицинский исследовательский центр им. В.А. Алмазова

Email: golovkin_a@mail.ru
ORCID iD: 0000-0002-7577-628X
SPIN-код: 8803-2425

д-р мед. наук

Россия, Санкт-Петербург

Ольга Михайловна Моисеева

Национальный медицинский исследовательский центр им. В.А. Алмазова

Email: moiseeva@almazovcentre.ru
ORCID iD: 0000-0002-7817-3847
SPIN-код: 1492-3900

д-р мед. наук, профессор

Россия, Санкт-Петербург

Игорь Владимирович Кудрявцев

Национальный медицинский исследовательский центр им. В.А. Алмазова

Email: igorek1981@yandex.ru
ORCID iD: 0000-0001-7204-7850
SPIN-код: 4903-7636

канд. биол. наук

Россия, Санкт-Петербург

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