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Delta-tocotrienol disrupts PD-L1 glycosylation and reverses PD-L1-mediated immune suppression
Zhenou Sun1, Xuan Ma2, Chong Zhao3
1College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China; College of Food Science and Nutritional Engineering, Tianjin University of Science and Technology, Tianjin, China.
Abstract:
PD-L1-mediated immune escape plays an important role in cancer development and progression. Targeting PD-L1 is consider to be an attractive approach for cancer treatment. PD-L1 is a heavily N-linked glycosylated protein, and the glycosylation of PD-L1 is essential for its ability to interact with its receptor PD-1 to mediate immune suppression. In the present study, we demonstrated for the first time that delta-tocotrienol (δ-T3) not any of the other forms of vitamin E was able to disrupt PD-L1 glycosylation mechanistically associated with the suppression of TCF4-STT3a/STT3b axis. The inhibition of PD-L1 glycosylation by δ-T3 resulted in the decrease of PD-L1 expression and its exosomal secretion, leading to the reduction of PD-L1 and PD-1 interaction, and reversing PD-L1-mediated immune suppression, which in turn contributed to the inhibitory effect on tumor growth. The findings of the present study provide a novel mechanistic interpretation for the superior anticancer activity of δ-T3 among 8 isomers of the vitamin E.
Insights
Delta-tocotrienol (δ-T3), a form of vitamin E, disrupts programmed death-ligand 1 (PD-L1) glycosylation. This inhibition reduces PD-L1 expression and immune suppression, offering a novel cancer treatment strategy.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Programmed death-ligand 1 (PD-L1) mediates immune escape in cancer development.
- PD-L1 glycosylation is crucial for its interaction with PD-1, leading to immune suppression.
- Targeting PD-L1 is a promising strategy for cancer therapy.
Purpose of the Study:
- To investigate the effect of delta-tocotrienol (δ-T3) on PD-L1 glycosylation and its role in cancer.
- To elucidate the mechanism by which δ-T3 inhibits PD-L1 function.
- To explore the potential of δ-T3 as an anticancer agent.
Main Methods:
- Investigated the impact of δ-T3 on PD-L1 glycosylation.
- Analyzed the TCF4-STT3a/STT3b axis in relation to PD-L1 glycosylation.
- Assessed PD-L1 expression, exosomal secretion, and PD-1 interaction.
- Evaluated the effect on tumor growth and immune suppression.
Main Results:
- δ-T3 specifically disrupts PD-L1 N-linked glycosylation via the TCF4-STT3a/STT3b pathway.
- Inhibition of PD-L1 glycosylation by δ-T3 led to decreased PD-L1 expression and secretion.
- δ-T3 reduced PD-L1/PD-1 interaction, reversing immune suppression.
- δ-T3 demonstrated superior anticancer activity compared to other vitamin E isomers.
Conclusions:
- δ-T3 effectively inhibits PD-L1 glycosylation, offering a novel mechanism for cancer treatment.
- The findings highlight δ-T3's unique role in disrupting the PD-L1/PD-1 axis.
- δ-T3 presents a promising therapeutic candidate for overcoming immune escape in cancer.
