d-mannose targets PD-1 to lysosomal degradation and enhances T cell-mediated anti-tumor immunity
Wenjing Dong1, Mingen Lin1, Ruonan Zhang1
1Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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.
Insights
D-mannose triggers programmed cell death protein 1 (PD-1) degradation, enhancing anti-tumor immunity. This discovery offers new strategies to improve cancer therapies like immune checkpoint blockade and MEK inhibitors.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Programmed cell death protein 1 (PD-1) is a key immune checkpoint that causes T cell dysfunction in the tumor microenvironment.
- Current PD-1/PD-L1 inhibitors are effective against various cancers, but PD-1 regulation mechanisms remain incompletely understood.
Purpose of the Study:
- To elucidate a novel mechanism for PD-1 degradation.
- To investigate the anti-tumor potential of d-mannose in conjunction with existing cancer therapies.
Main Methods:
- Investigated d-mannose's effect on PD-1 regulation in T cells.
- Utilized in vivo models to assess the combination therapy of d-mannose with PD-1 blockade and MEK inhibitors.
Main Results:
- D-mannose promotes PD-1 degradation by inactivating GSK3β, leading to TFE3 nuclear translocation and enhanced lysosome biogenesis.
- Combination therapy with d-mannose and PD-1 blockade significantly suppressed tumor growth by increasing T cell cytotoxicity.
- D-mannose enhanced the efficacy of trametinib (a MEK inhibitor) in vivo.
Conclusions:
- D-mannose destabilizes PD-1 through a novel degradation pathway, revealing an unrecognized anti-tumor mechanism.
- D-mannose represents a promising therapeutic strategy to augment the effectiveness of immune checkpoint blockade and MEK inhibitor-based cancer treatments.
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