Abstract

Death receptor (DR)-targeted therapies offer a promising tumor cell-specific therapeutic strategy for highly malignant brain tumors, such as glioblastoma (GBM). However, whether DR-mediated cell death leads to activation of the adaptive immune system and impacts the tumor immune microenvironment (TIME) remains unknown. In this study we explored the 1) immunomodulatory role of secretable human DR4/5 ligand, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (S-TRAIL); and 2) the therapeutic potential of allogeneic stem cells (SCs) delivered S-TRAIL and myeloid progenitor cell activating cytokine, FMS-like tyrosine kinase 3 ligand (FLT3L). We created syngeneic murine immune -active and -suppressive mouse GBM tumor models expressing a human-murine chimeric DR5. Next, we created therapeutic SCs that release FLT3L and S-TRAIL and assessed their efficacy in GBM tumor models. To facilitate clinical translation, we tested the mechanism-based efficacy of encapsulated SC-TRAIL/FLT3L in both syngeneic and humanized mouse tumor-models of GBM-resection. We show that S-TRAIL induced apoptosis in GBM cells provokes infiltration and maturation of dendritic cells (DC) within the TIME in vivo. Next, we show that local transplantation of encapsulated bimodal SCs post-surgical GBM-resection improves the survival probability and induces upregulation of conventional DC type 1 (cDC1) and CD8+ T cells. Furthermore, treatment with encapsulated off-the-shelf clinical-grade bimodal human SCs in GBM-bearing humanized mice results in a significant decrease in tumor-volumes. This study uncovers the immunological role of TRAIL-mediated cell death in the TIME and provides evidence for the encapsulated cell-based therapy to kill residual tumor-cells and induce long-term immunity.