T-cells can kill tumor cells by cell surface immunological recognition, but low affinity for tumor-associated antigens could lead to T-cell off-target effects. Thus it is crucial to search novel targeting strategies for further clinic application of T-cell immune therapeutics.

A research team led by Prof. CAI Lintao at the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences, developed a "universal T-cell targeting strategy" based on bio orthogonal chemistry and glycol-metabolic engineering to enhance recognition and cytotoxicity of T-cell in tumor immunotherapy.

Tumor heterogeneity represents an ongoing challenge in the field of cancer therapy. Therefore, conventional single-molecule targeting might be confronted with limitations for tumor targeting in clinic.

Prof. CAI’s group designed the unnatural cyclooctene (BCN) modified sugar (Ac4ManN-BCN) that can incorporated into surface glycans of various tumor cells, which marked BCN groups to be artificial targeting reporters of tumor. “This artificial targeting strategy can improve tumor-targeting ability by overcoming tumor heterogeneity, because these BCN groups make tumor cells more uniform.” Prof. CAI said, "This targeting strategy was also appropriate for T-cells therapy, for which, enhanced tumor targeting is just the urgent issue to be solved.”

Activated T-cells are treated with Ac4GalNAz to introduce azido (N3) on cell surface, initiating the specific tumor targeting through bioorthogonal click reaction between N3 and BCN. This artificial targeting strategy remarkably enhanced recognition and migration of T-cell to tumor cell, and increased 2 to 4 times cytotoxicity for T-cells against different kinds of tumor cells. T-cells even exhibited similar cytotoxicity with CAR-T cells against Raji cells in vitro at effector: target cell ratios (E:T) of 1:1.

"This universal T-cell-targeting strategy might further broaden applications of T-cell therapy against tumor". Prof. CAI said, “It also provides a new perspective for T-cell modification”.

The paper “Bio-orthogonal T-Cell Targeting Strategy For Robustly Enhancing Cytotoxicity Against Tumor Cells” is being published in Small, and is also selected as Hot topic. 

Fig. The universal T-cell-targeting strategy mediated by bioorthogonal glycolengineering for enhancing T-cell recognition and cytotoxicity to tumor cell.(Image by Prof. CAI)