miR-181d coordinates homologous recombination and anti-tumor immune responses in glioblastoma

Master regulatory microRNAs (miRNAs) are characterized by their ability to coordinate distinct yet interconnected pathways to drive transitions in cell states. In this study, we identify miR-181d as a master regulatory miRNA that coordinates acquired resistance and anti-tumoral immunity in glioblastoma, the most prevalent form of adult primary brain cancer. Profiling of miR-181d targets revealed RAD51, an essential gene for homologous recombination (HR). miR-181d binding to RAD51 mRNA, which suppresses RAD51 expression, was abolished by mutating the miR-181d binding site in the RAD51 3′ UTR. The radiation-sensitizing and HR-suppressing effects of miR-181d were epistatic to RAD51 in vitro and in vivo. Temozolomide (TMZ) treatment induced cross-resistance to radiation and acquired resistance to TMZ; both forms of resistance were eliminated by RAD51 silencing or miR-181d transfection. Finally, the exogenous introduction of miR-181d in an immunocompetent murine glioblastoma model before radiation treatment induced anti-glioblastoma immune memory. These results support consideration for miR-181d-based glioblastoma therapy.