Targeting DDX3X Triggers Antitumor Immunity via a dsRNA-Mediated Tumor-Intrinsic Type I Interferon Response

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.

circREEP3 Drives Colorectal Cancer Progression via Activation of FKBP10 Transcription and Restriction of Antitumor Immunity

“…[ 40 ] Accumulating reports have showed that intracellular dsRNA could activate innate immune response and stimulate production of type I IFN to prevent tumorigenesis. [ 41 , 42 ] A recent work reveals that circNDUFB2 activates anti‐tumor immunity to suppress lung cancer growth. [ 31 ] How circRNA regulates innate immunity in CRC is largely unknown.…”

A Dual Role of DDX3X in dsRNA-Derived Innate Immune Signaling

“…Our study suggests that DDX3X prevents antiviral response against endogenous dsRNAs in the steady-state cell condition (without a viral infection or synthetic dsRNA treatment) ( Choi et al, 2021 ). A small fraction of endogenous dsRNAs was detected in the cytoplasm.…”

“…We found that 1) loss of DDX3X or inhibiting DDX3X resulted in the aberrant accumulation of endogenous dsRNAs in the cytoplasm of breast cancer cells; 2) the accumulation of dsRNAs activated the dsRNA-sensing pathway via mainly MDA5 and activation of nuclear factor kappa B (NF-κB) pathway followed by IFN- β production and enhanced antigen presentation in the DDX3X-depleted cells; 3) DDX3X-depleted cancer cells demonstrated the inhibited cancer proliferation and suppressed tumor growth in in vivo mouse studies. DDX3X-depleted breast tumor also exhibited tumor-intrinsic innate immune activation and increased tumor-infiltrated cytotoxic T cells and DCs in a syngeneic mouse model ( Figure 1 ) ( Choi et al, 2021 ).…”

Biological Characterization and Clinical Value of OAS Gene Family in Pancreatic Cancer

“…In the present study, type I interferon signaling pathway is one result of GO enrichment analysis, its function has an important relationship with the function of pDCs. Choi et al (50) reported that activation of type I interferon is a novel approach to activate the immune system against cancer. NOD-like receptor (NLRs) signaling pathway is another important signaling pathway that is worthy of attention.…”