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Updated: Jul 20, 2025
Quantitative Immunohistochemistry of the Cellular Microenvironment in Patient Glioblastoma Resections
Published on: July 31, 2017
SEC61G assists EGFR-amplified glioblastoma to evade immune elimination
Kunlin Zeng1, Yu Zeng1, Hongchao Zhan1
1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
Abstract:
Amplification of chromosome 7p11 (7p11) is the most common alteration in primary glioblastoma (GBM), resulting in gains of epidermal growth factor receptor (EGFR) copy number in 50 to 60% of GBM tumors. However, treatment strategies targeting EGFR have thus far failed in clinical trials, and the underlying mechanism remains largely unclear. We here demonstrate that EGFR amplification at the 7p11 locus frequently encompasses its neighboring genes and identifies SEC61G as a critical regulator facilitating GBM immune evasion and tumor growth. We found that SEC61G is always coamplified with EGFR and is highly expressed in GBM. As an essential subunit of the SEC61 translocon complex, SEC61G promotes translocation of newly translated immune checkpoint ligands (ICLs, including PD-L1, PVR, and PD-L2) into the endoplasmic reticulum and promotes their glycosylation, stabilization, and membrane presentation. Depletion of SEC61G promotes the infiltration and cytolytic activity of CD8+ T cells and thus inhibits GBM occurrence. Further, SEC61G inhibition augments the therapeutic efficiency of EGFR tyrosine kinase inhibitors in mice. Our study demonstrates a critical role of SEC61G in GBM immune evasion, which provides a compelling rationale for combination therapy of EGFR-amplified GBMs.
Insights
SEC61G, coamplified with EGFR in glioblastoma, drives immune evasion by stabilizing immune checkpoint ligands. Inhibiting SEC61G enhances T cell activity and combination therapy for EGFR-amplified glioblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- The most common genetic alteration in glioblastoma (GBM) is chromosome 7p11 amplification, often leading to increased epidermal growth factor receptor (EGFR) copy number.
- Despite EGFR amplification in 50-60% of GBMs, EGFR-targeted therapies have shown limited clinical success, indicating a need to understand underlying resistance mechanisms.
Purpose of the Study:
- To investigate the role of genes coamplified with EGFR in GBM pathogenesis.
- To identify novel therapeutic targets for EGFR-amplified glioblastoma, particularly focusing on immune evasion mechanisms.
Main Methods:
- Analysis of gene coamplification patterns in GBM.
- Assessment of SEC61G expression and its function in immune checkpoint ligand (ICL) processing.
- In vivo studies involving SEC61G depletion and combination therapy in mouse models.
Main Results:
- SEC61G is consistently coamplified with EGFR and highly expressed in GBM, facilitating tumor immune evasion.
- SEC61G, as part of the SEC61 translocon, promotes the translocation, glycosylation, and membrane presentation of ICLs (PD-L1, PVR, PD-L2).
- SEC61G depletion enhances CD8+ T cell infiltration and activity, inhibiting GBM growth and augmenting EGFR tyrosine kinase inhibitor efficacy in mice.
Conclusions:
- SEC61G plays a critical role in mediating immune evasion in EGFR-amplified glioblastoma.
- Targeting SEC61G offers a promising strategy for combination therapy to improve treatment outcomes in GBM.
