Enriched Environment Cues Suggest a New Strategy to Counteract Glioma: Engineered rAAV2-IL-15 Microglia Modulate the Tumor Microenvironment

Abstract

Several types of cancer grow differently depending on the environmental stimuli they receive. In glioma, exposure to an enriched environment (EE) increases the overall survival rate of tumor-bearing mice, acting on the cells that participate to define the tumor microenvironment. In particular, environmental cues increase the microglial production of interleukin (IL)-15 which promotes a pro-inflammatory (antitumor) phenotype of microglia and the cytotoxic activity of natural killer (NK) cells, counteracting glioma growth, thus representing a virtuous mechanism of interaction between NK cells and microglia. To mimic the effect of EE on glioma, we investigated the potential of creating engineered microglia as the source of IL-15 in glioma. We demonstrated that microglia modified with recombinant adeno-associated virus serotype 2 (rAAV2) carrying IL-15 (rAAV2-IL-15), to force the production of IL-15, are able to increase the NK cells viability in coculture. Furthermore, the intranasal delivery of rAAV2-IL-15 microglia triggered the interplay with NK cells in vivo, enhancing NK cell recruitment and pro-inflammatory microglial phenotype in tumor mass of glioma-bearing mice, and ultimately counteracted tumor growth. This approach has a high potential for clinical translatability, highlighting the therapeutic efficacy of forced IL-15 production in microglia: the delivery of engineered rAAV2-IL-15 microglia to boost the immune response paves the way to design a new perspective therapy for glioma patients.