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Dl-3-N-Butylphthalide Presents Anti-Cancer Activity in Lung Cancer by Targeting PD-1/PD-L1 Signaling
Qian Jiang1,2,3, Nan Zhang2, Xin Li2
1Department of Head and Neck Oncology, Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
Introduction:
Lung cancer serves as one of the most malignant cancer types. Immunotherapy targeting PD-1/PD-L1 axis is a promising strategy for cancer treatment. Dl-3-N-butylphthalide (NBP), a small molecule compound extracted from the seeds of Apium graveolens, possesses a large range of biological effects and demonstrates anti-cancer activities. However, the role of NBP in the modulation of lung cancer remains obscure.
Methods:
In this study, we aimed to explore the effect of NBP on PD-L1 signaling and the progression of lung cancer.
Results:
Significantly, the treatment of NBP repressed the proliferation of lung cancer cells in vitro. Tumorigenicity analysis in nude mice showed that the tumor volume and tumor weight were attenuated by the treatment of NBP in the mice. Meanwhile, the levels of Ki-67 and PD-L1 were reduced by the treatment of NBP in the tumor tissues of the mice. NBP suppressed IFN-γ-induced PD-L1 enhancement in lung cancer cells. The treatment of NBP inhibited PD-L1 expression in lung cancer cells co-cultured with unstimulated PBMCs or activated T cell. NBP inhibited PD-1 expression in activated T cells co-cultured with lung cancer cells. Conditioned medium from activated T cells increased PD-L1 expression, and NBP reversed this effect. Co-culture with A549 and H1975 cells reduced T cell proliferation and activity, while the treatment of NBP reversed the reduction. Consistently, the treatment of NBP caused notably decreased apoptosis of co-cultured T cells. Mechanically, KAT7 was able to bind to PD-L1 promoter and epigenetically induce PD-L1 expression by promoting the enrichment of histone H3 lysine 14 acetylation (H3K14ac) and RNA polymerase II on PD-L1 promoter.
Discussion:
Thus, we concluded that NBP repressed PD-L1 expression by targeting KAT7 and attenuated PD-1/PD-L1 axis to relieve lung cancer progression. NBP may be applied as the potential therapeutic strategy in immunotherapy of lung cancer.
Insights
Dl-3-N-butylphthalide (NBP) inhibits lung cancer progression by repressing PD-L1 expression. This small molecule compound targets KAT7, attenuating the PD-1/PD-L1 axis and showing potential for lung cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Lung cancer is a highly malignant disease.
- Immunotherapy targeting the PD-1/PD-L1 axis is a key treatment strategy.
- Dl-3-N-butylphthalide (NBP) exhibits anti-cancer properties, but its role in lung cancer is unclear.
Purpose of the Study:
- To investigate the effect of NBP on PD-L1 signaling in lung cancer.
- To explore NBP's impact on lung cancer progression and the PD-1/PD-L1 axis.
Main Methods:
- In vitro cell proliferation assays.
- In vivo tumorigenicity studies in nude mice.
- Analysis of PD-L1, PD-1, Ki-67 expression, and T cell activity.
- Investigation of KAT7's role in PD-L1 epigenetic regulation.
Main Results:
- NBP treatment repressed lung cancer cell proliferation and reduced tumor growth, volume, and weight in mice.
- NBP suppressed PD-L1 expression in tumor tissues and lung cancer cells, even under IFN-γ stimulation.
- NBP inhibited PD-1 expression on T cells and improved T cell proliferation and activity, while reducing T cell apoptosis.
- NBP targets KAT7, which epigenetically induces PD-L1 expression via H3K14ac and RNA polymerase II enrichment on the PD-L1 promoter.
Conclusions:
- NBP represses PD-L1 expression by targeting KAT7, thereby attenuating the PD-1/PD-L1 axis and alleviating lung cancer progression.
- NBP demonstrates potential as a therapeutic strategy for lung cancer immunotherapy.
