染色体错分离诱导的RNA传感增强抗肿瘤免疫。 - Suppr | 超能文献

Abstract

Viral mimicry driven by endogenous double-stranded RNA (dsRNA) stimulates innate and adaptive immune responses. However, the mechanisms that regulate dsRNA-forming transcripts during cancer therapy remain unclear. Here, we demonstrate that dsRNA is significantly accumulated in cancer cells following pharmacologic induction of micronuclei, stimulating mitochondrial antiviral signaling (MAVS)-mediated dsRNA sensing in conjunction with the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. Activation of cytosolic dsRNA sensing cooperates with double-stranded DNA (dsDNA) sensing to upregulate immune cell migration and antigen-presenting machinery. Tracing of dsRNA-sequences reveals that dsRNA-forming transcripts are predominantly generated from non-exonic regions, particularly in locations proximal to genes exhibiting high chromatin accessibility. Activation of this pathway by pulsed monopolar spindle 1 (MPS1) inhibitor treatment, which potently induces micronuclei formation, upregulates cytoplasmic dsRNA sensing and thus promotes anti-tumor immunity mediated by cytotoxic lymphocyte activation in vivo. Collectively, our findings uncover a mechanism in which dsRNA sensing cooperates with dsDNA sensing to boost immune responses, offering an approach to enhance the efficacy of cancer therapies targeting genomic instability.

摘要

由内源性双链RNA（dsRNA）驱动的病毒模拟可刺激先天性和适应性免疫反应。然而，癌症治疗期间调节形成dsRNA的转录本的机制仍不清楚。在此，我们证明，在药理学诱导微核形成后，dsRNA在癌细胞中显著积累，与环状GMP-AMP合酶（cGAS）/干扰素基因刺激物（STING）途径一起刺激线粒体抗病毒信号（MAVS）介导的dsRNA感知。胞质dsRNA感知的激活与双链DNA（dsDNA）感知协同作用，上调免疫细胞迁移和抗原呈递机制。对dsRNA序列的追踪显示，形成dsRNA的转录本主要来自非外显子区域，特别是在染色质可及性高的基因附近的位置。通过脉冲单极纺锤体1（MPS1）抑制剂处理激活该途径，该抑制剂可有效诱导微核形成，上调细胞质dsRNA感知，从而在体内促进由细胞毒性淋巴细胞激活介导的抗肿瘤免疫。总的来说，我们的研究结果揭示了一种机制，即dsRNA感知与dsDNA感知协同作用以增强免疫反应，为提高针对基因组不稳定的癌症治疗疗效提供了一种方法。