Nature (2018)

The blood–brain barrier (BBB) forms a formidable vascular hurdle. Tumor endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which engages its counter-ligand CD6, expressed on activated T cells. However, tumor endothelium downregulates expression of the ICAM1 and VCAM1 adhesion molecules, thereby preventing sustained T cell adhesion and extravasation into brain tumors. In Nature, Samaha et al. engineer expression of synthetic CD6 molecules on cytolytic T cells to exploit the tumor-induced changes in brain endothelium to deliver tumor immunotherapies. Multimerization of the CD6 D3 exodomain, which recognizes ALCAM, increases the avidity of T cell binding to tumor endothelium but not to normal brain endothelium. Signaling via the CD6 endodomain elicits additional cytoskeletal changes in T cells to facilitate their extravasation into tumor tissue. Engineered T cells expressing tumor-specific chimeric antigen receptors (CAR T cells) and engineered CD6 molecules exhibit better control of glioblastoma than do control T cells in mouse models. These findings point to therapeutic strategies for attacking brain tumors.