Targeted inducible delivery of immunoactivating cytokines reprograms glioblastoma microenvironment and inhibits growth in mouse models [scRNA-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. Single-cell RNA-seq of CD45+ tumor-infiltrating (glioblastoma) mice cells belonging to control and gene therapy treated (IFN-a and IFN-a-DHFR) groups.