CD47 Knock-Out Using CRISPR-Cas9 RNA Lipid Nanocarriers Results in Reduced Mesenchymal Glioblastoma Growth In Vivo.

in Advanced science (Weinheim, Baden-Wurttemberg, Germany) by Nadia Rouatbi, Adam A Walters, Alaa Zam, Yau Mun Lim, Alessia Marrocu, Revadee Liam-Or, Joanne E Anstee, James N Arnold, Julie Tzu-Wen Wang, Steven M Pollard, Khuloud T Al-Jamal

TLDR

  • Researchers developed lipid nanoparticles (LNPs) encapsulating CRISPR RNAs as an in vivo screening tool for immune checkpoint proteins (ICPs) in a syngeneic model of mesenchymal glioblastoma cancer stem cells (GSCs).

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.

Overview

  • The study aims to develop lipid nanoparticles (LNPs) encapsulating CRISPR RNAs as an in vivo screening tool for immune checkpoint proteins (ICPs) in a syngeneic model of mesenchymal glioblastoma cancer stem cells (GSCs).
  • The study uses PD-L1 and CD47 as validation targets to demonstrate the proof of concept in orthotopic tumors, demonstrating efficient editing of ICPs and enhanced immune cell infiltration within the tumor microenvironment.
  • The primary objective of the study is to position LNPs as a robust tool for in vivo validation of ICPs as therapeutic targets in clinically relevant glioblastoma models, potentially expediting ICP translation and enhancing personalized glioblastoma immunotherapies.

Comparative Analysis & Findings

  • The study demonstrates that intratumoral administration of LNPs encapsulating CRISPR RNAs leads to efficient editing of ICPs, enhancing immune cell infiltration within the tumor microenvironment.
  • Targeting CD47 using LNPs reduces tumor growth, suggesting improved cancer cell sensitization to the immune system post-ICP editing.
  • The study validates the use of LNPs as a proof of concept for ICPs in mesenchymal GSCs, highlighting the potential for LNPs as a screening tool for ICP combinations in patient-derived xenografts.

Implications and Future Directions

  • The study positions LNPs as a robust tool for in vivo validation of ICPs as therapeutic targets in clinically relevant glioblastoma models, potentially expediting ICP translation and enhancing personalized glioblastoma immunotherapies.
  • Future studies can build on the results of this study by exploring the use of LNPs in combination with other immunotherapies or investigating the use of LNPs in different glioblastoma subtypes.
  • The study highlights the need for further investigation into the role of ICPs in glioblastoma and their potential as therapeutic targets, as well as the development of LNPs as a screening tool for ICP combinations in patient-derived xenografts.
Read Full Article