Bio‐Orthogonal T Cell Targeting Strategy for Robustly Enhancing Cytotoxicity against Tumor Cells

作者：Wenjun Li, Hong Pan, Huamei He, Xiaoqing Meng, Qian Ren, Ping Gong, Xin Jiang, Zhenguo Liang, Lanlan Liu, Mingbin Zheng, Ximing Shao, Yifan Ma, Lintao Cai · 发表于：Small · 年份：2018 · DOI：10.1002/smll.201804383 · 被引用次数：58 · 研究领域：CAR-T cell therapy research、Click Chemistry and Applications、Cancer Research and Treatments

Abstract 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. Herein, a universal T cell targeting strategy based on bio‐orthogonal chemistry and glycol‐metabolic engineering is introduced to enhance recognition and cytotoxicity of T cells in tumor immunotherapy. Three kinds of bicycle [6.1.0] nonyne (BCN)‐modified sugars are designed and synthesized, in which Ac 4 ManN‐BCN shows efficient incorporation into wide tumor cells with a BCN motif on surface glycans. Meanwhile, activated T cells are treated with Ac 4 GalNAz to introduce azide (N 3 ) on the cell surface, initiating specific tumor targeting through a bio‐orthogonal click reaction between N 3 and BCN. This artificial targeting strategy remarkably enhances recognition and migration of T cells to tumor cells, and increases the cytotoxicity 2 to 4 times for T cells against different kinds of tumor cells. Surprisingly, based on this strategy, the T cells even exhibit similar cytotoxicity with the chimeric antigen receptor T‐cell against Raji cells in vitro at the effector: target cell ratios (E:T) of 1:1. Such a universal bio‐orthogonal T cell‐targeting strategy might further broaden applications of T cell therapy against tumors and provide a new strategy for T cell modification.