1. Targeting DDX3X Triggers Antitumor Immunity via a dsRNA-Mediated Tumor-Intrinsic Type I Interferon Response.
- Author
-
Choi H, Kwon J, Cho MS, Sun Y, Zheng X, Wang J, Bouker KB, Casey JL, Atkins MB, Toretsky J, and Han C
- Subjects
- Animals, Apoptosis, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Breast Neoplasms prevention & control, Cell Proliferation, DEAD-box RNA Helicases genetics, DEAD-box RNA Helicases metabolism, Female, Humans, Interferon Type I metabolism, Interferon-Induced Helicase, IFIH1 genetics, Mice, Mice, Inbred BALB C, Mice, Nude, Prognosis, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Breast Neoplasms immunology, DEAD-box RNA Helicases antagonists & inhibitors, Gene Expression Regulation, Neoplastic, Immunity, Innate immunology, Interferon Type I immunology, Interferon-Induced Helicase, IFIH1 metabolism, RNA, Double-Stranded genetics
- Abstract
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 antitumor 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. SIGNIFICANCE: This study elucidates the novel role of DDX3X in regulating endogenous cellular dsRNA homeostasis and type I IFN signaling in breast cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/13/3607/F1.large.jpg., (©2021 American Association for Cancer Research.)
- Published
- 2021
- Full Text
- View/download PDF