Single-cell RNA-seq-based proteogenomics identifies glioblastoma-specific transposable elements encoding...

Area of Science:

• Genomics
• Immunology
• Oncology

Background:

• Transposable elements (TEs) are mobile genetic sequences that can alter genome structure and gene expression.
• Glioblastoma (GBM) is an aggressive primary brain tumor with limited effective treatment options.
• Identifying tumor-specific targets is crucial for developing effective cancer immunotherapies.

Purpose of the Study:

• To investigate the role and potential therapeutic targeting of transposable elements (TEs) in glioblastoma (GBM).
• To identify novel GBM-specific peptides derived from TEs that can be presented by human leukocyte antigen (HLA)-I molecules.

Main Methods:

• Utilized a proteogenomic pipeline integrating single-cell transcriptomics, bulk RNA sequencing (RNA-seq) of tumor and healthy tissues, and immunopeptidomic analyses.
• Analyzed differential expression of TEs in GBM patient samples compared to healthy controls.
• Identified HLA-I-bound peptides encoded by differentially expressed TEs in GBM.

Main Results:

• Identified 370 unique HLA-I-bound peptides encoded by TEs differentially expressed in GBM.
• Discovered peptides derived from intact open reading frames (ORFs) in recent TE subfamilies (LINE-1, LTR, SVA).
• Found peptides from ancient TE subfamilies expressed recurrently and specifically in GBM tumors, but not in healthy tissues.

Conclusions:

• Recurrently expressed, GBM-specific TEs and their encoded peptides represent potential tumor-specific targets.
• These findings suggest a novel avenue for developing targeted cancer immunotherapies for glioblastoma.
• The proteogenomic approach provides a powerful framework for discovering TE-derived antigens in cancer.