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CD47 Knock-Out Using CRISPR-Cas9 RNA Lipid Nanocarriers Results in Reduced Mesenchymal Glioblastoma Growth In Vivo
Nadia Rouatbi1, Adam A Walters1, Alaa Zam1
1Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
Abstract:
Immune checkpoint (ICP) blockade has shown limited effectiveness in glioblastoma (GBM), particularly in the mesenchymal subtype, where interactions between immune cells and glioblastoma cancer stem cells (GSCs) drive immunosuppression and therapy resistance. Tailoring ICPs specific to GSCs can enhance the antitumor immune response. This study proposes the use of lipid nanoparticles (LNPs) encapsulating CRISPR RNAs as an in vivo screening tool for ICPs in a syngeneic model of mesenchymal GSCs. Using PD-L1 and CD47 to validate the proof of concept, intratumoral administration of LNPs in orthotopic tumors achieved efficient editing of ICPs, leading to enhanced immune cell infiltration within the tumor microenvironment. Targeting CD47 reduced tumor growth, suggesting improved cancer cell sensitization to the immune system post-ICP editing. The study positions LNPs as a robust tool for in vivo validation of ICPs as therapeutic targets in clinically relevant GBM models. LNPs could serve as a screening tool in patient-derived xenografts to identify and optimize ICP combinations, potentially expediting ICP translation and enhancing personalized GBM immunotherapies.
Insights
Lipid nanoparticles (LNPs) with CRISPR RNA efficiently screen immune checkpoints (ICPs) in glioblastoma stem cells. This approach enhances immune infiltration and reduces tumor growth, paving the way for personalized glioblastoma immunotherapies.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Immune checkpoint (ICP) blockade shows limited efficacy in glioblastoma (GBM), especially mesenchymal subtypes, due to immunosuppression driven by glioblastoma stem cells (GSCs).
- Targeting GSC-specific ICPs is crucial for enhancing antitumor immune responses in GBM.
Purpose of the Study:
- To develop and validate lipid nanoparticles (LNPs) encapsulating CRISPR RNAs as an in vivo screening tool for ICPs in mesenchymal GSCs.
- To assess the therapeutic potential of editing ICPs like PD-L1 and CD47 in a syngeneic GBM model.
Main Methods:
- Utilized LNPs delivering CRISPR RNAs for in vivo screening of ICPs in a syngeneic model of mesenchymal GSCs.
- Administered LNPs intratumorally in orthotopic GBM tumors, focusing on PD-L1 and CD47 targets.
- Evaluated immune cell infiltration and tumor growth post-editing.
Main Results:
- Achieved efficient editing of ICPs within orthotopic tumors via intratumoral LNP administration.
- Observed enhanced immune cell infiltration into the tumor microenvironment after ICP editing.
- Targeting CD47 demonstrated reduced tumor growth, indicating improved immune sensitization.
Conclusions:
- LNPs serve as a robust platform for in vivo validation of ICPs as therapeutic targets in GBM.
- This LNP-based screening approach can accelerate the identification and optimization of ICP combinations for personalized GBM immunotherapies.
