ASGR2 and CLEC12A as Prognostically Relevant C-Type Lectin Hubs in Glioblastoma

Area of Science:

• Immunology and Oncology
• Molecular Biology and Bioinformatics

Background:

• Glioblastoma (GB) exhibits profound tumor immune microenvironment (TME) immunosuppression, hindering therapeutic efficacy, particularly immunotherapies.
• An intricate network involving tumor cells, stroma, and immune cells sustains this immunosuppression.
• Lectins, as immunoregulatory glycan-binding receptors, significantly contribute to immunosuppression and represent potential anti-cancer therapeutic targets.

Purpose of the Study:

• To leverage network-based approaches to identify a specific lectin profile within the glioblastoma TME.
• To dissect the complex tumor-immunity interactions and pinpoint key lectins involved in immunosuppression.
• To evaluate the potential of identified lectins as therapeutic targets for glioblastoma.

Main Methods:

• Differential co-expression analysis was performed using transcriptomic data from TCGA, CGGA, and GTEx databases (total 533 samples).
• Network analysis identified hub lectins, specifically ASGR2 and CLEC12A, within the glioblastoma immune microenvironment.
• TIMER2.0 analysis correlated lectin expression with immune cell infiltration; ASGR2 and CLEC12A expression was further validated using cytofluorimetric analysis on patient tumor and liquid biopsies.

Main Results:

• A novel cluster of C-type lectins, with ASGR2 and CLEC12A as key regulators, was identified.
• Expression of ASGR2 and CLEC12A was significantly associated with immunosuppressive immune cells, particularly myeloid subsets.
• ASGR2 and CLEC12A expression levels correlated with poor prognosis in glioblastoma patients and were validated in patient samples.

Conclusions:

• ASGR2 and CLEC12A C-type lectins are implicated in the immunosuppressive network driven by infiltrating myeloid cells in glioblastoma.
• These lectins serve as potential biomarkers for patient prognosis and represent promising, exploitable targets for novel glioblastoma therapeutic interventions.