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Overexpression of GLT1D1 induces immunosuppression through glycosylation of PD‐L1 and predicts poor prognosis in B‐cell lymphoma
- Source :
- Molecular Oncology, Vol 14, Iss 5, Pp 1028-1044 (2020), Molecular Oncology
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
Abstract
- B‐cell non‐Hodgkin's lymphoma (NHL) is a class of heterogeneous diseases with variable clinical outcomes. Immunosuppression is particularly common in the subtypes of lymphoma with poor prognosis, but the underlying mechanism remains unclear. Using a RT‐PCR array analysis, we have identified that glycosyltransferase 1 domain‐containing 1 (GLT1D1), an enzyme that transfers glycosyl groups to proteins, is highly upregulated in the incurable subtype of B‐cell NHL and in early relapse diffuse large B‐cell lymphoma. Analysis of clinical specimens revealed that GLT1D1 expression was positively correlated with the level of glycosylated programmed cell death‐ligand 1 (PD‐L1) in B‐cell NHL and that high GLT1D1 expression was associated with poor prognosis. Mechanistically, we showed that GLT1D1 transferred N‐linked glycans to PD‐L1, thus promoting the immunosuppressive function of glycosylated PD‐L1. Downregulation of GLT1D1 resulted in a decrease of glycosylated PD‐L1 and enhanced cytotoxic T‐cell function against lymphoma cells. In vivo, overexpression of GLT1D1 promoted tumor growth by facilitating tumor immune escape through increased levels of PD‐L1. Our work has identified GLT1D1 as a predictive biomarker for B‐cell NHL. It has also shown that this enzyme enhances PD‐L1 stabilization via N‐glycosylation, thus promoting immunosuppression and tumor growth. As such, GLT1D1 might be a novel therapeutic target for the treatment of B‐NHL.<br />B‐cell non‐Hodgkin's lymphoma (B‐NHL) is a heterogeneous group of diseases with different biological characteristics and clinical outcomes. The expression of glycosyltransferase 1 domain‐containing 1 (GLT1D1) in B‐NHL was positively correlated with the level of glycosylated PD‐L1, and high GLT1D1 expression was associated with poor prognosis. GLT1D1 transferred N‐glycans to the asparagine residue of PD‐L1 and thus enhances its stability, leading to immunosuppression and poor clinical outcome.
- Subjects :
- 0301 basic medicine
Cancer Research
Glycosylation
Carcinogenesis
medicine.medical_treatment
T-Lymphocytes
Cell
CD8-Positive T-Lymphocytes
B7-H1 Antigen
chemistry.chemical_compound
Mice
0302 clinical medicine
immune system diseases
hemic and lymphatic diseases
Databases, Genetic
Cytotoxic T cell
RNA, Small Interfering
B-cell lymphoma
Research Articles
immunosuppression
biology
Tunicamycin
Immunosuppression
General Medicine
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Molecular Medicine
Female
Lymphoma, Large B-Cell, Diffuse
Research Article
Lymphoma, B-Cell
Cell Survival
B‐cell non‐Hodgkin's lymphoma
lcsh:RC254-282
03 medical and health sciences
Downregulation and upregulation
Polysaccharides
PD-L1
Cell Line, Tumor
Genetics
medicine
Biomarkers, Tumor
Animals
Humans
Immunosuppression Therapy
business.industry
medicine.disease
GLT1D1
Coculture Techniques
Lymphoma
Mice, Inbred C57BL
030104 developmental biology
chemistry
glycosylated PD‐L1
Cancer research
biology.protein
prognosis
CRISPR-Cas Systems
business
Subjects
Details
- Language :
- English
- ISSN :
- 15747891 and 18780261
- Volume :
- 14
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Molecular Oncology
- Accession number :
- edsair.doi.dedup.....56491e4481d3b249291cc8deb6de7200