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Glycodelin: A New Biomarker with Immunomodulatory Functions in Non-Small Cell Lung Cancer
Marc A Schneider1, Martin Granzow2, Arne Warth3
1Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany. Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
Purpose:
In recent years, immune therapeutic strategies against non-small cell lung cancer (NSCLC) based on tissue-derived biomarkers, for example PD1/PD-L1 (CD274), have evolved as novel and promising treatment options. However, the crosstalk between tumor and immune cells is poorly understood. Glycodelin (gene name PAEP), initially described in the context of pregnancy and trophoblastic implantation, is a secreted immunosuppressive glycoprotein with an as-of-yet largely unknown function in lung cancer.
Experimental Design:
In this study, we characterized the expression and role of glycodelin in NSCLC through mRNA and protein expression analyses, functional knockdown experiments, and correlations with clinicopathologic parameters.
Results:
Glycodelin mRNA expression was significantly elevated in tumors (n = 336) compared with matched normal tissue (P < 0.0001). Overall survival (OS) was significantly reduced in NSCLC with high glycodelin mRNA levels in women but not in men. Glycodelin was detected in the sera of patients, and the levels correlated with recurrence and metastatic disease. Knockdown of glycodelin with siRNAs in NSCLC cell lines resulted in significant upregulation of immune system modulatory factors such as PDL1, CXCL5, CXCL16, MICA/B, and CD83 as well as proliferation stimulators EDN1 and HBEGF. Furthermore, decreased migration of tumor cells was observed.
Conclusions:
Altogether, the comprehensive characterization of glycodelin in NSCLC provides strong support for its use as a biomarker with immune modulatory function.
Insights
Glycodelin, a protein involved in immune suppression, is elevated in non-small cell lung cancer (NSCLC). High glycodelin levels correlate with reduced survival in women and increased recurrence, suggesting its potential as a diagnostic biomarker.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint inhibitors targeting PD1/PD-L1 (CD274) are advancing non-small cell lung cancer (NSCLC) treatment.
- The complex interactions between tumor and immune cells in NSCLC remain incompletely understood.
- Glycodelin (PAEP), an immunosuppressive glycoprotein, has an undefined role in lung cancer.
Purpose of the Study:
- To investigate the expression and functional significance of glycodelin in NSCLC.
- To explore glycodelin's potential as a biomarker in NSCLC.
Main Methods:
- Analysis of glycodelin mRNA and protein expression in NSCLC tissues and sera.
- Functional studies using siRNA-mediated knockdown in NSCLC cell lines.
- Correlation analysis with clinicopathologic parameters and patient survival.
Main Results:
- Glycodelin mRNA levels were significantly higher in NSCLC tumors versus normal tissue.
- Elevated glycodelin mRNA correlated with reduced overall survival in female NSCLC patients.
- Serum glycodelin levels indicated associations with disease recurrence and metastasis.
- Glycodelin knockdown upregulated immune modulators (e.g., PDL1, CXCL5, CXCL16) and proliferation factors, and decreased tumor cell migration.
Conclusions:
- Glycodelin plays a role in modulating the immune microenvironment and tumor cell behavior in NSCLC.
- Comprehensive characterization supports glycodelin's utility as a biomarker in NSCLC.
- Glycodelin's immune modulatory functions offer potential therapeutic implications for NSCLC treatment.
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