Self-adjuvant nanovaccine delivering cytokines as a novel platform to empower glioblastoma immunotherapy

Abstract

Abstract Glioblastoma (GBM) is a highly aggressive and deadly malignant primary brain tumor with a median survival time of less than 15 months upon disease diagnosis. While immunotherapies have shown promising results in solid cancers, brain cancers are still unresponsive to immunotherapy due to immunological dysfunction and the presence of a blood-brain barrier. Interleukin (IL)-12 is one of the most potent cytokines used for anti-tumor immunity due to the stimulation of interferon-gamma production by T and natural killer cells and changing macrophages to a tumoricidal phenotype. However, IL-12 toxicity is well reported when systemically administered to patients in clinical trials. To overcome this major drawback, we have formulated a novel self-adjuvant nanovaccine composed of immunostimulatory nanoparticles (ISN) loaded with IL-12 to decrease IL-12 toxicity and promote the expression of pro-inflammatory cytokines by macrophages and GBM cancer cells. Our in vitro results demonstrate that ISN were able to stimulate the production of pro-inflammatory cytokines in GBM cancer cells and macrophages, suggesting possible modulation of the tumor microenvironment. We also demonstrate that ISN successfully delivered intracellularly IL-12, changing the intracellular levels of pro-inflammatory cytokines at the transcriptional and protein expression levels. These results suggest that self-adjuvant nanovaccine might be a promising platform for modulating the glioblastoma microenvironment, empowering immunotherapy.