RIG-I RNA agonist activates immunostimulatory macrophages to enhance checkpoint immunotherapy for glioblastoma

Glioblastoma (GBM), the most frequent and aggressive primary brain tumor, remains refractory to all current therapies including surgical resection, chemotherapy, radiotherapy and immunotherapy. Immunosuppressive mechanisms in the GBM tumor microenvironment contribute to the lack of anti-tumor adaptive immunity. We found that a subset of tumor associated macrophages (TAMs) can be repolarized into an anti-tumor phenotype via agonist stimulation of the retinoic acid-inducible gene I (<i>RIGI</i>), a cytosolic double-stranded RNA pattern recognition receptor (PRR). In silico analysis of adult GBM datasets available in the public domain revealed that <i>RIGI</i> expression by a subset of activated TAMs positively correlated with patient survival. Studies in syngeneic mouse models of GBM showed that intratumoral delivery of stem-loop RNA 14 (SLR14), a RIG-I agonist, improved the efficacy of chemotherapy, radiotherapy and immunotherapy treatments, beyond the effects of other nuclei acid sensor agonists. We found that <i>RIGI</i> ⁺ macrophages are the main drivers of SLR14 effect, combining activation of TAMs and priming of functional cytotoxic CD8⁺ T lymphocytes and NK cells. The anti-GBM effect of SLR14 is opening a significant new avenue for adult GBM treatment.