Heparanase-Loaded CAR T Extracellular Vesicles Remodel the Colorectal Tumour Microenvironment and Boost T Cell Antitumor Immunity - PubMed
3 hours ago
- #extracellular matrix
- #colorectal cancer
- #CAR T therapy
- Engineered mesothelin-targeted CAR T cells to express heparanase (HPSE) fused to pX domain for surface display on extracellular vesicles, enabling localized, pH-dependent ECM degradation in acidic tumor microenvironments.
- HPSE CAR T cells penetrated ECM mimics nearly fourfold more effectively than standard CAR T cells and exhibited enhanced tumor killing via increased expression of TRAIL, FasL, and perforin in colorectal cancer models.
- HPSE CAR T-derived extracellular vesicles retained CAR and chemokine receptors (CCR5/CCR7), carried apoptotic ligands, and promoted T cell proliferation, CCR5 expression, and memory formation while reducing PD-1 and CD57.
- In HCT116 xenografts, HPSE CAR T cells increased intratumoral infiltration, and their EVs boosted host T cell infiltration, reducing tumor burden, extending survival beyond 70 days without systemic toxicity.
- The study demonstrates a dual strategy of ECM remodeling and immune modulation, offering a translational approach to overcome barriers to CAR T therapy in colorectal cancer.