Browsing by Subject "Double-stranded RNAs"

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    Targeting DDX3X Triggers Antitumor Immunity via a dsRNA-Mediated Tumor-Intrinsic Type I Interferon Response
    (American Association for Cancer Research, 2021) Choi, Hyeongjwa; Kwon, Juntae; Cho, Min Soon; Sun, Yifan; Zheng, Xiaofeng; Wang, Jing; Bouker, Kerrie B.; Casey, John L.; Atkins, Michael B.; Toretsky, Jeffrey; Han, Cecil; Medical and Molecular Genetics, School of Medicine
    Induction of nucleic-acid sensing-mediated type I interferon (IFN) has emerged as a novel approach to activate the immune system against cancer. Here we show that the depletion of DEAD-box RNA helicase 3X (DDX3X) triggers a tumor-intrinsic type I IFN response in breast cancer cells. Depletion or inhibition of DDX3X activity led to aberrant cytoplasmic accumulation of cellular endogenous double-stranded RNAs (dsRNA), which triggered type I IFN production through the melanoma differentiation-associated gene 5 (MDA5)-mediated dsRNA sensing pathway. Furthermore, DDX3X interacted with dsRNA-editing ADAR1 and dual depletion of DDX3X and ADAR1 synergistically activated the cytosolic dsRNA pathway in breast cancer cells. Loss of DDX3X in mouse mammary tumors enhanced anti-tumor activity by increasing the tumor-intrinsic type I IFN response, antigen presentation, and tumor-infiltration of cytotoxic T and dendritic cells. These findings may lead to the development of a novel therapeutic approach for breast cancer by targeting DDX3X in combination with immune checkpoint blockade.