激动剂激活RIG-I+肿瘤相关巨噬细胞可增强胶质母细胞瘤的抗肿瘤免疫和治疗应答

Glioblastoma (GBM), the most frequent and aggressive primary tumor of the brain, escapes all standard-of-care treatments that are provided after resection, including chemotherapy, radiotherapy or immunotherapy. The GBM tumor microenvironment is regulated by immunosuppressive mechanisms of the innate immune system, thereby contributing to the lack of anti-tumor adaptive immunity. We found that tumor associated macrophages (TAMs) can be repolarized into a M1 anti-tumor phenotype via agonist stimulation of the retinoic acid-inducible gene I (RIG-I), a cytosolic double-stranded RNA pattern recognition receptor (PRR). Innate immunity is governed by PRRs, which act as sensors of foreign and danger-associated molecular patterns and initiate the innate immune response. In silico analysis of adult GBM datasets available in the public domain revealed that RIGI-I expression by a subset of activated M1 TAMs positively correlated with patient survival. Studies in syngenic mouse models of GBM showed that intratumoral delivery of stem-loop RNA 14 (SLR14), a RIG-I agonist, improved the efficacy of all standard anti-GBM treatments, beyond the effects of other nuclei acid sensor agonists. We found that the combined activation of M1 TAMs and priming of functional cytotoxic CD8 + T lymphocytes and NK cells were accounting for the anti-GBM effect of SLR14, opening a significant new avenue for adult GBM treatment.