Science immunology · 2026
Treg cells promote immunotherapy-induced immune evasion by restraining CD4 T cell control of MHC-I-deficient metastatic pancreatic cancer.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Schmiechen Zoe C, Cruz-Hinojoza Eduardo, Hilk Audrey L, Ellefson Madeline A, Tsai Alexander K, Dres Olivia M, Kang Liang-I, Geuenich Michael J, Butler Jonah Z, Burrack Adam L, Larsen Brandon M, Hickok Grant H, Miller Ebony A, Lonetree Cara-Lin, Gaire Amrit, Pandey Rachana, Nanda Hezkiel A, Chaudhury Indrajit, Corbiere Thomas, Dileepan Thamotharampillai, Shen Steven S, Campbell Kieran R, DeNardo David G, Stromnes Ingunn M
Аннотация
Mechanisms driving immunotherapy resistance in pancreatic cancer are poorly defined. We demonstrate that programmed death-ligand 1 immune checkpoint blockade promoted immune evasion by epigenetic Tap1 (transporter associated with antigen processing 1) silencing, increasing selection of metastatic tumor variants with defective interferon-γ (IFN-γ)-inducible class I major histocompatibility complex (MHC-I) expression. Unleashing CD4 conventional T cells by regulatory T cell (Treg cell) depletion, transfer of tumor-reactive CD4 T cells, or anti-CTLA-4 prevented metastasis. Tumor-specific CD4 T cells adopted a TCF-1+SLAMF6+ progenitor state in lymph nodes and differentiated in tumors. Anti-CTLA-4 increased intratumoral accumulation of CD4 T cells with stemness and tissue residency features, reduced metastasis, and induced gene signatures correlated with improved patient outcomes. MHC-I restoration with anti-CTLA-4 prolonged survival in murine models. In patient tumors, Treg cells and CD4 T cells colocalized, and abundance correlated with survival. These findings identify targetable mechanisms of immune evasion and metastasis in immunotherapy-resistant cancer.