生物
先天免疫系统
RNA解旋酶A
应力颗粒
解旋酶
核糖核酸
RNA沉默
细胞生物学
病毒学
RNA干扰
遗传学
翻译(生物学)
免疫系统
基因
信使核糖核酸
作者
Takahiko Murayama,Jun Nakayama,Xinpei Jiang,Kenichi Miyata,Alexander D. Morris,Kathy Q. Cai,Rahul M. Prasad,Xiaopin Ma,Andrey Efimov,Neel Belani,Emily R. Gerstein,Yinfei Tan,Yan Zhou,William Kim,Reo Maruyama,Kerry S. Campbell,Lu Chen,Yibin Yang,Siddharth Balachandran,Israel Cañadas
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2024-01-08
被引量:2
标识
DOI:10.1158/2159-8290.cd-23-0486
摘要
Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as "viral mimicry", has emerged as an effective strategy to convert immunologically "cold" tumors into "hot". Through a curated CRISPR-based screen of RNA Helicases, we identified DExD/H-box helicase 9 (DHX9) as a potent repressor of double-stranded RNA (dsRNA) in small cell lung cancers (SCLCs). Depletion of DHX9 induced accumulation of cytoplasmic dsRNA and triggered tumor-intrinsic innate immunity. Intriguingly, ablating DHX9 also induced aberrant accumulation of R-loops, which resulted in an increase of DNA damage-derived cytoplasmic DNA and replication stress in SCLCs. In vivo, DHX9 deletion promoted decrease in tumor growth while inducing a more immunogenic tumor microenvironment, invigorating responsiveness to immune checkpoint blockade. These findings suggest that DHX9 is a crucial repressor of tumor-intrinsic innate immunity and replication stress, representing a promising target for SCLC and other "cold" tumors where genomic instability contribute to pathology.
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