Targeting DDX3X triggers anti-tumor immunity via a dsRNA-mediated tumor-intrinsic type I interferon response

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-05, Vol.81 (13), p.3607-3620
• Main Authors: 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
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-20-3790

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.