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bioRxiv · 10.1101/2023.12.19.572484

Lactose and its derivatives are a new class of immune checkpoint inhibitors for cancer therapy

Hong, Y.·Si, X.·Liu, W.·Mai, X.·Zhang, Y.
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Abstract

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.

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Hong, Y., Si, X., Liu, W., Mai, X., Zhang, Y.. 2023-12-20. Lactose and its derivatives are a new class of immune checkpoint inhibitors for cancer therapy. https://doi.org/10.1101/2023.12.19.572484

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