Redirecting Killer T Cells through Incorporation of Azido Sugars for Tethering Ligands.
The genetic expression of chimeric antigen receptors (CARs) on the surfaces of T cells enables the redirection of T cell specificity. To enhance the versatility of T cells as tumor-specific killers, we developed a nongenetic approach by which azide-containing sialic acids were metabolically incorporated into T cells to modify cellular sialyl glycans. After successful display of these moieties on the T cells, small-molecule ligands such as RGD and folate (as proof-of-concept, rather than supersized antibodies) were clicked orthogonally, leading to highly selective time- and dose-dependent cytotoxicity to integrin αv β3 - and folate-receptor-positive cells, respectively. This chemical approach provides a facile platform for rational design of tumor-specific cytotoxic T cells for targeted immunotherapy.