Lactose and its derivatives are a new class of immune checkpoint inhibitors for cancer therapy
biorxiv(2023)
摘要
Understanding the mechanisms by which the immune system surveils cancer is the key to developing better tumor immunotherapy strategies. By CRISPR/Cas9 screenings, we identified that inactivation of beta-1,4-galactosyltransferase-1 (B4GALT1), a key enzyme in glycoconjugate biosynthesis, leads to enhanced T-cell receptor (TCR) activation and functions of CD8+ T-cells. Via proximity-dependent-intercellular-protein-spreading (PDICPS), cancer cells transfer surface-bound galectin-1 (Gal-1) proteins, which recognize and bind galactosylated membrane proteins, to CD8+ T-cells, thereby suppressing T-cell-mediated cytolysis. B4GALT1-deficiency leads to reduced cell-surface galactosylation and Gal-1 binding of CD8+ T-cells. Proteomic analysis revealed reduced binding of Gal-1 with TCR and its coreceptor CD8 on B4GALT1-deficient CD8+ T-cells, leading to enhanced TCR-CD8 colocalization and T-cell activation. Lactose, a structure-mimicking competitive inhibitor of N-glycan galactosylation, enhances the functions of CD8+ T-cells and tumor immunosurveillance. Results from various preclinical tumor models demonstrate that lactose and its derivatives are a new class of immune checkpoint inhibitors for tumor immunotherapy.
### Competing Interest Statement
Part of this research has been submitted for patents.
更多查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要