Oncogenic KRAS drives immunosuppression of colorectal cancer by impairing DDX60-mediated dsRNA accumulation and viral mimicry

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2024-10-04 DOI:10.1126/sciimmunol.ado8758

Yi Zhou, Yaxin Zhang, Mingzhou Li, Tian Ming, Chao Zhang, Chengmei Huang, Jiexi Li, Fengtian Li, Huali Li, Enen Zhao, Feng Shu, Lingtao Liu, Xingyan Pan, Yijun Gao, Lin Tian, Libing Song, Huilin Huang, Wenting Liao

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引用次数: 0

Abstract

The interferon (IFN) response is vital for the effectiveness of immune checkpoint inhibition (ICI) therapy. Our previous research showed that KRAS (Kirsten rat sarcoma viral) mutation impairs the IFN response in colorectal cancer (CRC), with an unclear mechanism. Here, we demonstrate that KRAS accelerates double-stranded RNA (dsRNA) degradation, impairing dsRNA sensing and IFN response by down-regulating DExD/H-box helicase 6 (DDX60). DDX60 was identified as a KRAS target here and could bind to dsRNAs to protect against RNA-induced silencing complex (RISC)–mediated degradation. Overexpressing DDX60 induced dsRNA accumulation, reactivated IFN signaling, and increased CRC sensitivity to ICI therapy. Mechanistically, KRAS engaged the AKT (also known as protein kinase B)–GSK3β (glycogen synthase kinase-3 beta) pathway to suppress STAT3 phosphorylation, thereby inhibiting STAT3-driven DDX60 transcription. Our findings reveal a role for KRAS in dsRNA homeostasis, suggesting potential strategies to convert “cold” tumors to “hot” and to overcome ICI resistance in CRC with KRAS mutations.

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致癌 KRAS 通过损害 DDX60 介导的 dsRNA 积累和病毒拟态，驱动结直肠癌的免疫抑制作用

干扰素（IFN）反应对免疫检查点抑制（ICI）疗法的有效性至关重要。我们之前的研究表明，KRAS（Kirsten大鼠肉瘤病毒）突变会损害结直肠癌（CRC）的IFN反应，其机制尚不清楚。在这里，我们证明了KRAS通过下调DExD/H-box螺旋酶6（DDX60）加速双链RNA（dsRNA）降解，损害dsRNA感应和IFN反应。DDX60 在这里被确定为 KRAS 的靶标，它可以与 dsRNA 结合，防止 RNA 诱导的沉默复合体（RISC）介导的降解。过表达 DDX60 会诱导 dsRNA 积累，重新激活 IFN 信号，并增加 CRC 对 ICI 治疗的敏感性。从机理上讲，KRAS通过AKT（又称蛋白激酶B）-GSK3β（糖原合酶激酶-3 beta）途径抑制STAT3磷酸化，从而抑制STAT3驱动的DDX60转录。我们的研究结果揭示了 KRAS 在 dsRNA 平衡中的作用，为将 "冷 "肿瘤转化为 "热 "肿瘤以及克服 KRAS 突变的 CRC 对 ICI 的耐药性提出了潜在的策略。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.