Tmic-12. Tumor-homing Rna-nanoparticles Reprogram Immune Cells in the Brain Tumor Microenvironment
Year: 2018
Type: conference-abstract
Abstract: Brain tumors are particularly difficult to treat due to their relative isolation behind the blood brain barrier. Cytotoxic T cells elicited by cancer vaccines are capable of penetrating this barrier, but are limited by innate immune cells in tumor microenvironments that inhibit T cell function. There is therefore an unmet need for a method to reprogram the immune cells in the tumor microenvironment to promote antitumor T cell responses. We previously reported that systemically administered liposomes bearing RNA encoding tumor antigens profoundly activate innate immune cells in reticuloendothelial system (RES) organs. Here, we report a modified liposome formulation capable of redirecting this immunomodulatory nucleic acid cargo to immune cells in brain tumors. Cationic liposomes with varying compositions were loaded with Cy3-labelled RNA or siRNA and injected intravenously into glioma-bearing mice. RNA uptake was assessed with flow cytometry and immunofluorescence microscopy after 18 hours. Inclusion of cholesterol within liposomes increased mRNA uptake in intracranial GL261 and KR158b tumors after systemic injection in a dose-dependent manner. Optimized tumor-homing liposomes delivered mRNA encoding tumor antigens to CD45+ immune cells in both tumors. These liposomes were also used to deliver siRNA against programmed death ligand 1 (PDL1). siRNA-loaded liposomes reduced PDL1 expression on dendritic cells ex vivo and on transfected CD45+ cells in murine brain tumors. Our optimized liposomes effectively deliver mRNA and siRNA to immune cells in multiple murine brain tumors. Future work will consider the mechanism of this enhanced delivery and the use of tumor-homing liposomes to deliver other immunomodulatory biomolecules.
Source: Neuro-Oncology
Institutions: University of Florida Health, University of Florida
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2900025145