Targeted inducible delivery of immunoactivating cytokines reprograms glioblastoma microenvironment and inhibits growth in mouse models [Bulk RNA-seq]. Targeted inducible delivery of immunoactivating cytokines reprograms glioblastoma microenvironment and inhibits growth in mouse models [Bulk RNA-seq]

We exploited a lentiviral vector-based platform to engineer hematopoietic stem cells ex vivo with the aim of releasing, via their tumor-infiltrating monocyte/macrophage progeny, IFN-a or IL-12 at the tumor site in a spatial and temporal regulated manner. Taking advantage of a syngeneic GBM mouse model, we showed that inducible release of IFN-a within the TME achieved robust tumor inhibition up to eradication and outperformed systemic treatment with the recombinant protein in terms of efficacy, tolerability and specificity. Single-cell RNAseq of the tumor immune infiltrate revealed reprogramming of the immune microenvironment towards a pro-inflammatory and anti-tumoral state associated with loss of a macrophage subpopulation predicting poor prognosis in human GBM. Overall design: Bulk RNA-seq of sorted glioblastoma cells (GFP+) and unaffected brain hemisphere samples of IFN-a-DHFR gene therapy treated, recombinant IFN-a1 treated, and control mice.