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.