RNA sensing induced by chromosome missegregation augments anti-tumor immunity III

We demonstrate that dsRNA is significantly accumulated in cancer cells following pharmacologic induction of micronuclei, stimulating MAVS-mediated dsRNA sensing in conjunction with the cGAS/STING pathway. Activation of cytosolic dsRNA sensing co-operates with dsDNA sensing to up-regulate immune cell migration and antigen-presenting machinery. Tracing of dsRNA-sequence identity revealed 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) kinase inhibitor therapy, which potently induces micronuclei formation, thus induces cytoplasmic dsRNA-sensing and promotes anti-tumor immunity mediated by type I interferon signaling and cytotoxic lymphocyte activation in vivo. Taken together, these findings reveal a novel aspect of the dsRNA-sensing pathway in enhancing the anti-tumor efficacy of drugs that promote genomic instability and micronuclei formation, facilitating cancer immunogenicity. Overall design: We invetigated MAVS-dependent gene expression alteration of tumor tissue following pulsed MPS1 treatment.

本研究证实，经药物诱导微核形成后，癌细胞内会显著积累双链RNA（dsRNA），并与cGAS/STING通路协同激活线粒体抗病毒信号蛋白（MAVS）介导的双链RNA感知过程。细胞质双链RNA感知的激活与双链DNA感知协同作用，可上调免疫细胞迁移及抗原呈递相关机制。对双链RNA序列同一性的溯源分析显示，形成双链RNA的转录本主要源自非外显子区域，尤其富集于染色质开放性较高的基因邻近位点。通过脉冲式施用可强效诱导微核形成的单极纺锤体1（MPS1）激酶抑制剂，可激活该通路，进而诱导细胞质双链RNA感知，并在体内促进由I型干扰素信号通路与细胞毒性淋巴细胞活化介导的抗肿瘤免疫。综上，本研究揭示了双链RNA感知通路的全新功能：其可增强促进基因组不稳定与微核形成的药物的抗肿瘤疗效，进而提升肿瘤的免疫原性。实验设计：本研究探究了脉冲式MPS1处理后，肿瘤组织中MAVS依赖的基因表达变化。