Targeting DDX3X Triggers Antitumor Immunity via a dsRNA-Mediated Tumor-Intrinsic Type I Interferon Response
| Autor: | Michael B. Atkins, Min Soon Cho, Kerrie B. Bouker, John L. Casey, Jing Wang, Hyeongjwa Choi, Jeffrey A. Toretsky, Cecil Han, Xiaofeng Zheng, Juntae Kwon, Yifan Sun |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Interferon-Induced Helicase IFIH1 Antigen presentation Mice Nude Apoptosis Breast Neoplasms Article DEAD-box RNA Helicases 03 medical and health sciences Mice 0302 clinical medicine Immune system Interferon medicine Biomarkers Tumor Tumor Cells Cultured Cytotoxic T cell Animals Humans Cell Proliferation RNA Double-Stranded Mice Inbred BALB C Chemistry Melanoma Cancer MDA5 medicine.disease Prognosis RNA Helicase A Xenograft Model Antitumor Assays Immunity Innate Gene Expression Regulation Neoplastic Survival Rate 030104 developmental biology Oncology 030220 oncology & carcinogenesis Interferon Type I Cancer research Female medicine.drug |
| Zdroj: | Cancer Res |
| ISSN: | 1538-7445 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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