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d-mannose targets PD-1 to lysosomal degradation and enhances T cell-mediated anti-tumor immunity.
- Source :
-
Cancer letters [Cancer Lett] 2024 Jun 01; Vol. 591, pp. 216883. Date of Electronic Publication: 2024 Apr 12. - Publication Year :
- 2024
-
Abstract
- High expression of programmed cell death protein 1 (PD-1), a typical immune checkpoint, results in dysfunction of T cells in tumor microenvironment. Antibodies and inhibitors against PD-1 or its ligand (PD-L1) have been widely used in various malignant tumors. However, the mechanisms by which PD-1 is regulated are not fully understood. Here, we report a mechanism of PD-1 degradation triggered by d-mannose and the universality of this mechanism in anti-tumor immunity. We show that d-mannose inactivates GSK3β via promoting phosphorylation of GSK3β at Ser9, thereby leading to TFE3 translocation to nucleus and subsequent PD-1 proteolysis induced by enhanced lysosome biogenesis. Notably, combination of d-mannose and PD-1 blockade exhibits remarkable tumor growth suppression attributed to elevated cytotoxicity activity of T cells in vivo. Furthermore, d-mannose treatment dramatically improves the therapeutic efficacy of MEK inhibitor (MEKi) trametinib in vivo. Our findings unveil a universally unrecognized anti-tumor mechanism of d-mannose by destabilizing PD-1 and provide strategies to enhance the efficacy of both immune checkpoint blockade (ICB) and MEKi -based therapies.<br />Competing Interests: Declaration of competing interest The authors declare no competing interests.<br /> (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Humans
Mice
Cell Line, Tumor
Tumor Microenvironment drug effects
Tumor Microenvironment immunology
Immune Checkpoint Inhibitors pharmacology
Glycogen Synthase Kinase 3 beta metabolism
Pyrimidinones pharmacology
Phosphorylation
Pyridones pharmacology
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism
Mice, Inbred C57BL
Proteolysis
Neoplasms immunology
Neoplasms drug therapy
Neoplasms pathology
Neoplasms metabolism
Programmed Cell Death 1 Receptor metabolism
Lysosomes metabolism
T-Lymphocytes immunology
T-Lymphocytes drug effects
T-Lymphocytes metabolism
Mannose pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 591
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 38615929
- Full Text :
- https://doi.org/10.1016/j.canlet.2024.216883