Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx
The dense glycocalyx of cancer cells can restrict immune-cell access to surface antigens and limit CAR-T cell activity. Here, we show that mucin density and epitope position determine how glycocalyx remodeling affects CAR-T cell recognition and killing. We identify KLK5 as a human protease that cleaves tumor-associated mucins, increases access to membrane-proximal antigens, and enhances CAR-T…
The dense glycoprotein layer, or glycocalyx, surrounding cancer cells can obstruct immune cells from reaching and binding to specific antigens on the cell surface, thus inhibiting the action of CAR-T cells. A recent study reveals that the density of mucins and their positioning on the cell surface play a crucial role in determining how glycocalyx remodeling impacts CAR-T cell recognition and killing.
Researchers have identified KLK5, a human protease enzyme, which cleaves tumor-associated mucins, thereby increasing the accessibility of membrane-proximal antigens and boosting CAR-T cell functionality. To harness this potential, the scientists engineered CAR-T cells to either display or secrete KLK5, facilitating the remodeling of the tumor's glycocalyx during antigen recognition.
CAR-T cells engineered to express or secrete KLK5 demonstrated enhanced tumor control in various xenograft models. Among these, CAR-T cells that secreted KLK5, specifically those targeting the MUC17 antigen, exhibited the most significant improvement in survival rates compared to conventional MUC17 CAR-T cells. These findings suggest that engineering CAR-T cells to breach the mucin-rich glycocalyx while maintaining access to essential target epitopes could significantly enhance the effectiveness of CAR-T cell therapy.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
