ALG3 predicts poor prognosis and increases resistance to anti-PD-1 therapy through modulating PD-L1 N-link glycosylation in TNBC

Bo Luo ¹, Xiangdong Liu ², Qu Zhang ³

⁰Department of Radiotherapy Center, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Clinical Research Center for Breast Cancer, Wuhan, Hubei, China; Wuhan Clinical Research Center for Breast Cancer, Wuhan, Hubei, China.

International Immunopharmacology +

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August 8, 2024

View abstract on PubMed

Summary

Alpha-1,3-mannitrotransferase (ALG3) is elevated in triple-negative breast cancer (TNBC), correlating with poor prognosis and reduced immunotherapy efficacy. Lowering ALG3 expression may improve treatment outcomes in TNBC.

Area Of Science

Oncology
Molecular Biology
Immunotherapy

Background

Triple-negative breast cancer (TNBC) presents a significant clinical challenge with limited targeted therapies.
Understanding novel biomarkers and therapeutic targets is crucial for improving TNBC patient outcomes.
The role of glycosylation in cancer progression and immune evasion warrants further investigation.

Purpose Of The Study

To assess the prognostic significance of alpha-1,3-mannitrotransferase (ALG3) in TNBC.
To investigate ALG3's impact on the efficacy of anti-PD-1 therapy.
To elucidate the potential mechanisms underlying ALG3's influence on TNBC and immunotherapy.

Main Methods

Bioinformatics analysis of gene expression and patient databases (UACLAN, bc-GenExMiner, Kaplan-Meier Plotter, cBioPortal).
Immunohistochemistry (IHC) and western blot to analyze ALG3 expression and PD-L1 glycosylation.
CRISPR/Cas9 gene editing to create ALG3 low-expression TNBC cell lines.
In vitro assays for proliferation and chemosensitivity, and in vivo animal models for immunotherapy response.

Main Results

Elevated ALG3 expression in TNBC is linked to unfavorable clinical features and shorter overall survival.
High ALG3 expression negatively correlates with CD8+, CD4+, and NK cell infiltration.
Reduced ALG3 expression enhances sensitivity to chemotherapy and anti-PD-1 therapy, partly by decreasing PD-L1 glycosylation and increasing tumor cell sensitivity to IFN-γ.

Conclusions

ALG3 serves as a potential biomarker for poor prognosis in TNBC.
ALG3 may diminish immunotherapy efficacy by altering the tumor microenvironment and PD-L1 glycosylation.
Targeting ALG3 could represent a novel strategy to enhance immunotherapy response in TNBC.

Keywords:

ALG3 Immunotherapy PD-L1 Prognosis Triple negative breast cancer

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