Pluto Bioinformatics

GSE150003: ATR inhibition potentiates ionizing radiation-induced innate immunity via sensing cytosolic RNA

Bulk RNA sequencing

Radiotherapy, widely used for cancer treatment for decades, is revitalizing through its ability to induce systemic anti-tumor immune response via type I interferon signaling, especially in combination with immune checkpoint blockade. Mechanistic understanding of how ionizing radiation induces type I interferon signaling and how to amplify this signaling module will be highly instructive in maximizing the efficacy of radiotherapy. Here we found that ATR inhibitors, which are currently being developed as anti-cancer agent, can significantly potentiate ionizing radiation-induced immune response. Using a series of knockout cell lines we generated for components in cytosolic nucleic acid sensing pathways, we demonstrated that the MAVS-dependent cytosolic RNA sensing pathway is the major pathway responsible for ionizing radiation alone or ATR inhibitor plus ionizing radiation-induced type I interferon signaling in human cells. Consistently, over-expression of double-stranded RNA specific endoribonuclease RNase III derived from E. coli, but not DNA exonuclease TREX1, impaired type I IFN signaling. In addition, reconstitution of lamin B1 can significantly inhibit ATR inhibitor plus ionizing radiation-induced type I interferon signaling, indicating the possibility that micronuclei formation and the subsequent micronuclei disruption is required for this process. Moreover, ATR-CHK1-CDC25C axis dependent G2/M DNA damage checkpoint abrogation is required for ATR inhibitor plus ionizing radiation-induced type I interferon signaling. Our studies suggest that ATR inhibition in combination with radiotherapy and immune checkpoint blockade will be a promising new combination therapy against cancer. SOURCE: Junjie Chen UT MD Anderson Cancer Center