Rational design of immune gene therapy combinations via in vivo CRISPR activation screen of tumor microenvironment modulators - PubMed
3 hours ago
- #Tumor Microenvironment
- #Immunotherapy
- #CRISPR
- Rational design of immune gene therapy combinations via in vivo CRISPR activation screen of tumor microenvironment modulators.
- TME-targeted in vivo CRISPR activation (CRISPRa) screen identifies factors promoting anti-tumor immunity.
- Multiplexed activation of genes (APCM) enhances anti-tumor responses by improving antigen presentation, T cell proliferation, co-stimulation, and migration.
- Top immunostimulatory candidates identified: CD80, TNFSF14, CXCL10, TNFSF18, TNFSF9, and IFNG.
- Optimized therapeutic combination: TNFSF9 (4-1BBL) + IFNG + IL12B (4II).
- AAV-4II enhances antigen presentation, T cell activation, proliferation, cytotoxicity, and tumor infiltration.
- Preconditioning TME with AAV-4II synergizes with CAR-T and TCR-T cell therapies to suppress primary and metastatic solid tumors.
- TME-targeted CRISPRa screening accelerates development of immune gene therapy combinations for solid tumors.