Targeting DDX3X Triggers Antitumor Immunity via a dsRNA-Mediated Tumor-Intrinsic Type I Interferon Response.
Targeting DDX3X Triggers Antitumor Immunity via a dsRNA-Mediated Tumor-Intrinsic Type I Interferon Response.
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DOI：
10.1158/0008-5472.can-20-3790
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发表时间：
2021-07-01
期刊：
影响因子：
11.2
通讯作者：
Han C
中科院分区：
文献类型：
--
作者：
Choi H;Kwon J;Cho MS;Sun Y;Zheng X;Wang J;Bouker KB;Casey JL;Atkins MB;Toretsky J;Han C
诱导核酸传感介导的I型干扰素（IFN）已成为激活免疫系统对抗癌症的新方法。在这里，我们表明，DEAD盒RNA解旋酶3X（DDX3X）的耗尽触发乳腺癌细胞中的肿瘤内在I型IFN反应。DDX3X活性的消耗或抑制导致细胞内源性双链RNA（dsRNA）的异常细胞质积累，其通过黑素瘤分化相关基因5（MDA5）介导的dsRNA传感途径触发I型IFN产生。此外，DDX3X与dsRNA编辑ADAR 1相互作用，DDX3X和ADAR 1的双重消耗协同激活乳腺癌细胞中的胞质dsRNA途径。小鼠乳腺肿瘤中DDX3X的缺失通过增加肿瘤内在I型IFN应答、抗原呈递以及细胞毒性T细胞和树突状细胞的肿瘤浸润来增强抗肿瘤活性。这些发现可能导致通过靶向DDX3X与免疫检查点阻断相结合来开发一种新的乳腺癌治疗方法。
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.