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Updated: Jul 11, 2025
Detection of Alternative Splicing During Epithelial-Mesenchymal Transition
Published on: October 9, 2014
Challenges in the discovery of tumor-specific alternative splicing-derived cell-surface antigens in glioma
Background:
Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter-and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of neoantigens.
Results:
In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface neoantigens that could be targeted by antibodies and chimeric antigen receptor (CAR)-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas [TCGA]) and 9,166 normal tissue samples (from the Genotype-Tissue Expression project [GTEx]), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN , which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative neoantigens.
Conclusions:
Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.
Insights
Tumor-specific alternative splicing (AS) in glioma offers potential neoantigens, but their spatiotemporal heterogeneity and lack of protein detection pose challenges for immunotherapy development.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Solid tumors, including glioma, present significant challenges for cancer immunotherapy due to tumor heterogeneity.
- Targeting tumor-specific alternative splicing (AS) is a potential strategy to identify novel neoantigens.
- Neoantigens derived from AS events could be targeted by antibodies or chimeric antigen receptor (CAR)-T cells.
Conclusions:
- Tumor-specific AS events in glioma exhibit complex characteristics, including significant spatiotemporal heterogeneity.
- The elusive nature of these AS-derived neoantigens at the protein level presents challenges for therapeutic targeting.
- Future immunotherapy efforts may benefit from focusing on intracellular, MHC-presented antigens.
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