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Updated: Jan 8, 2026
Translational Orthotopic Models of Glioblastoma Multiforme
Published on: February 17, 2023
C/EBPβ-induced alternative splicing of RCAN1 generates a potent TCR-T target in mesenchymal glioblastoma
Zujian Xiong1,2, Qinglin Kong2, Bhuvitha Chagantipati2
1Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Abstract:
Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options and a dismal prognosis. While immunotherapy has shown promise in treating some solid tumors, the treatment of GBM has been mostly unsuccessful because of a lack of targetable tumor antigens and high tumor heterogeneity. Here, we report RCAN1-4 as a novel tumor antigen derived from alternative splicing induced by the transcription factor C/EBPβ. Both C/EBPβ and RCAN1-4 are highly expressed in GBM and glioma stem cells as mesenchymal subtype hallmarks. We report an immunogenic HLA-A24-specific splicing junction epitope within exon 4 and exon 5 that is unique to RCAN1-4. This epitope was validated for its ability to stimulate T cell responses in HLA-A24+ donors and GBM patients, leading us to identify RCAN1-4-reactive T cell receptors (TCRs) for the construction of TCR-engineered T cells (TCR-T cells). Functional studies of TCR-Ts demonstrated the in vitro and in vivo killing of RCAN1-4pos GBM tumor cells, highlighting its potential as an immunotherapeutic target in mesenchymal GBM.
Insights
Researchers identified RCAN1-4, a novel tumor antigen in glioblastoma (GBM), arising from alternative splicing. This discovery offers a promising new target for immunotherapy in mesenchymal GBM by enabling the development of T cell-based therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis and limited treatment options.
- Current immunotherapies are largely ineffective against GBM due to a lack of targetable antigens and tumor heterogeneity.
Purpose of the Study:
- To identify novel tumor antigens for GBM immunotherapy.
- To explore the therapeutic potential of RCAN1-4 in mesenchymal GBM.
Main Methods:
- Identified RCAN1-4 as a novel tumor antigen resulting from alternative splicing induced by C/EBPβ.
- Characterized an immunogenic HLA-A24-specific splicing junction epitope within RCAN1-4.
- Validated T cell responses to the epitope in HLA-A24+ donors and GBM patients.
- Developed RCAN1-4-reactive T cell receptors (TCRs) for engineered T cell (TCR-T) therapy.
Main Results:
- RCAN1-4 and C/EBPβ are highly expressed in GBM and glioma stem cells, particularly in the mesenchymal subtype.
- An immunogenic epitope unique to RCAN1-4 was identified and validated.
- RCAN1-4-reactive TCR-T cells demonstrated effective killing of RCAN1-4+ GBM cells in vitro and in vivo.
Conclusions:
- RCAN1-4 represents a novel and promising immunotherapeutic target for mesenchymal GBM.
- TCR-T cell therapy targeting RCAN1-4 shows potential for treating glioblastoma.
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