Next-generation immunogenic dendritic cell vaccines achieve a danger signaling and T cell-driven eradication of high-grade glioma

Abstract

Two decades of translational research substantiates the promise of dendritic cell (DC)-based immunotherapy. Of the four malignancies mostly targeted with clinical DC immunotherapy, high-grade glioma (HGG) has shown the highest susceptibility. However, HGG-induced immunosuppression is an anti-immunotherapy roadblock as evident by the observation that HGG may fail to respond to CTLA-4 or IDO1 immune-checkpoint blockade. This raises precedence for application of Th1 immunity-biased, next-generation, DC immunotherapy. To this end, we combined DC immunotherapy with immunogenic cell death (ICD; a modality shown to induce Th1-immunity), induced by hypericin-photodynamic therapy. In an orthotopic-HGG mouse model involving prophylactic/curative set-ups, both biologically and clinically-relevant versions of ICD-based DC vaccines provided remarkable anti-HGG survival benefit. The vaccine-induced HGG rejection was dependent upon, (proximally) the cancer cell and DC interface established through ROS and danger signals (secreted HMGB1>secreted ATP>surface-CRT); and (distally) on an intact adaptive immune system (especially, CD8+ T cells). In curative setting, ICD-based DC vaccines synergized with standard-of-care chemotherapy (temozolomide) to increase survival of HGG-bearing mice by ˜300% resulting in ˜50% long-term survivors. Additionally, these vaccines also induced an immunostimulatory shift in brain immune-contexture (increased Th1/cytotoxic T lymphocytes/Th17-cells and decreased Tregs) that had strong positive prognostic relevance in glioblastoma patients. This is the first translational study combining a single-agent ICD inducer with DC immunotherapy against orthotopic HGG.