期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2216796120
关键词
O-GlcNAcylation; cancer immune evasion; PD-L1; intracellular trafficking
Programmed-death ligand 1 (PD-L1) and its receptor programmed cell death 1 (PD-1) play a role in T cell-mediated immune response against tumors. The regulation of cell surface PD-L1 is not well understood, but it is shown in this study that lysosomal degradation of PD-L1 is regulated by O-linked N-acetylglucosamine (O-GlcNAc). Inhibition of O-GlcNAc activates T cell-mediated anti-tumor immunity and combining it with PD-L1 antibody enhances the immune response. A competitive peptide inhibitor of HGS glycosylation decreases PD-L1 expression and enhances T cell-mediated immunity against tumor cells. This study reveals a link between O-GlcNAc and tumor immune evasion, providing strategies for improving PD-L1-mediated immune checkpoint blockade therapy.
Programmed-death ligand 1 (PD-L1) and its receptor programmed cell death 1 (PD-1) mediate T cell-dependent immunity against tumors. The abundance of cell surface PD-L1 is a key determinant of the efficacy of immune checkpoint blockade therapy targeting PD-L1. However, the regulation of cell surface PD-L1 is still poorly understood. Here, we show that lysosomal degradation of PD-L1 is regu-lated by O-linked N-acetylglucosamine (O-GlcNAc) during the intracellular traffick-ing pathway. O-GlcNAc modifies the hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), a key component of the endosomal sorting machinery, and subsequently inhibits its interaction with intracellular PD-L1, leading to impaired lysosomal degradation of PD-L1. O-GlcNAc inhibition activates T cell-mediated antitumor immunity in vitro and in immune-competent mice in a manner dependent on HGS glycosylation. Combination of O-GlcNAc inhibition with PD-L1 antibody synergistically promotes antitumor immune response. We also designed a competitive peptide inhibitor of HGS glycosylation that decreases PD-L1 expression and enhances T cell-mediated immunity against tumor cells. Collectively, our study reveals a link between O-GlcNAc and tumor immune evasion, and suggests strategies for improving PD-L1-mediated immune checkpoint blockade therapy.
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