Dataset Information

FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer.

ABSTRACT: Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.

SUBMITTER: Huang Y

PROVIDER: S-EPMC8113546 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer.

Huang Yun Y Zhang Hai-Liang HL Li Zhi-Ling ZL Du Tian T Chen Yu-Hong YH Wang Yan Y Ni Huan-He HH Zhang Kai-Ming KM Mai Jia J Hu Bing-Xin BX Huang Jun-Hao JH Zhou Li-Huan LH Yang Dong D Peng Xiao-Dan XD Feng Gong-Kan GK Tang Jun J Zhu Xiao-Feng XF Deng Rong R

Nature communications 20210511 1

Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppressi ...[more]

PMID: 33976130

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Project description:Triple-negative breast cancer (TNBC) presents limited therapeutic options and is characterized by a poor prognosis. Although Kinsenoside (KIN) possesses a wide range of pharmacological activities, its effect and mechanism in TNBC remain unclear. The objective of this research was to explore the therapeutic effectiveness and the molecular mechanisms of KIN on TNBC. Xenograft experiment was carried out to assess the impact of KIN on TNBC in vivo. The effect of KIN on TNBC in vitro was evaluated through the analysis of cell cytotoxicity and colony formation assays. Oil Red O staining and BODIPY 493/503 fluorescence staining were employed to detect the effect of KIN on lipid droplet (LD) formation. Transcriptomics and inhibitor-rescue experiments were conducted to investigate the role of KIN on TNBC. Mechanistic experiments, including quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting, diacylglycerol acyltransferase 1 (DGAT1) overexpression assay, and flow cytometric assay, were employed to uncover the regulatory mechanisms of KIN on TNBC. KIN inhibited tumor growth without causing obvious toxicity to the liver and kidneys. In vitro experiments demonstrated that KIN significantly inhibited the viability and proliferation of TNBC cells, accompanied by decreased LD formation and lipid content. Polyunsaturated fatty acids (PUFAs) levels were significantly increased by KIN. Furthermore, transcriptomics and inhibitor-rescue experiments revealed that KIN induced ferroptosis in TNBC cells. KIN could significantly regulate ferroptosis-related proteins. Lipid peroxidation, iron accumulation, and GSH depletion also confirmed this. The LD inducer mitigated the KIN-induced ferroptosis in TNBC. The overexpression of DGAT1 attenuated the effects of KIN on cell viability and proliferation. Furthermore, the overexpression of DGAT1 inhibited the effect of KIN to trigger ferroptosis in TNBC cells. Our findings confirmed that KIN could trigger ferroptosis by suppressing DGAT1-mediated LD formation, thereby demonstrating a promising therapeutic effect of KIN in TNBC.

Dataset Information

FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer.

Publications

FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer.

Similar Datasets

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