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Transcript-targeted antigen mapping reveals the potential of POSTN splicing junction epitopes in glioblastoma immunotherapy

Genes & Immunity volume 26, pages 190–199 (2025)Cite this article

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Abstract

Tumor antigens are crucial for T-cell mediated immunotherapy, but identified antigens for gliomas remain limited. Aberrant splicing variants are commonly expressed in tumors, resulting in unique tumor isoforms with potential antigenic properties. Herein, we analyzed multi-omics data from 587 glioma patients and assembled a library of putative tumor-enriched isoform antigens (TIA) and corresponding peptides presented on each HLA-I allele. We constructed an individual-specific TIA peptide candidate repertoire for each patient based on their TIA expression and HLA-I haplotypes. TIAs were highly expressed, enriched with glioma malignancy, and demonstrated strong HLA-binding affinity. We focused on periostin isoform-203 (POSTN-203), which was associated with poor survival of patients and contained multiple predicted HLA-restricted peptide epitopes. A selected HLA-A11-restricted peptide from POSTN-203 (POSTN-203A11) induced antigen-specific T-cell responses against both peptide-pulsed and POSTN-203-expressing glioma cells in an HLA-specific manner. Our findings highlight TIAs as a promising source of immunogenic antigens and POSTN-203 as a potential promising target for glioma immunotherapy.

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Fig. 1: TIA identification and its distribution.
Fig. 2: TIA peptides were presented on MHC-I molecules in glioma.
Fig. 3: POSTN-203 (ENST00000379747) is a good TIA candidate for GBM.
Fig. 4: Immunogenicity test on POSTN-203 derived candidate TIA peptide.
Fig. 5: POSTN-203A11-primed T-cell responses rely on time and T-cell density.

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Data availability

The datasets generated and/or analyzed during the current study are available in the TCGA (https://www.cancer.gov/tcga/), CGGA (https://www.cgga.org.cn), and SRA (https://www.ncbi.nlm.nih.gov/sra/) repository.

Code availability

The code used in this study is available from the corresponding author upon reasonable request.

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Acknowledgements

This work was made possible through the generous support from the Botha-Chan Research Fund (IFP, GK), Brain Tumor Funders’ Collaborative (IFP, GK), the Ellie Kavalieros DIPG Research Fund (IFP, GK), Haley Weiss Memorial Fund (IFP, GK), and the Scientific Program Fund of the UPMC Children’s Hospital Foundation (IFP, GK). This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483.

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Authors and Affiliations

  1. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Zujian Xiong & Xuejun Li

  2. Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    Zujian Xiong, Chaim T. Sneiderman, Chloe R. Kuminkoski, Jared Reinheimer, ReidAnn E. Sever, Ahmed Habib, Baoli Hu, Sameer Agnihotri, Pascal O. Zinn, Ian F. Pollack, Itay Raphael & Gary Kohanbash

  3. Xiangya School of Medicine, Central South University, Changsha, Hunan, China

    Zujian Xiong

  4. Department of Molecular Microbiology and Immunology, University of Texas at San Antonio, San Antonio, TX, USA

    Lance Schwegman & Thomas G. Forsthuber

  5. Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA

    Dhivyaa Rajasundaram

  6. Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Xuejun Li

  7. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Gary Kohanbash

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Contributions

ZX conceptualized the study, designed the analysis workflow, conducted the data analysis and experiment validation, reviewed the data and assisted with data interpretation, and drafted the manuscript. CTS assisted with the experiment. CRK assisted with the experiment. JR assisted with the experiment. LS assisted with the experiment. RES assisted with the experiment. AH assisted with the experiment. BH reviewed the data and assisted with data interpretation. SA conceptualized the study. DR reviewed the data and assisted with data analysis and interpretation. POZ reviewed the data and assisted with data interpretation. TGF reviewed the data and assisted with data interpretation. IFP reviewed the data and assisted with data interpretation. XL reviewed the data and assisted with data interpretation and supervised the study. IR designed the analysis workflow, assisted with the experiment, reviewed the data and assisted with data interpretation, and drafted the manuscript. GK conceptualized the study, designed the analysis workflow, reviewed the data and assisted with data interpretation, supervised the study, and drafted the manuscript. All authors reviewed, edited, and approved the final manuscript.

Corresponding author

Correspondence to Gary Kohanbash.

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This study was conducted in compliance with the University of Pittsburgh Institutional Review Board guidelines as an exempt study. All participants provided their written informed consent (STUDY24050018). All methods were performed in accordance with the relevant guidelines and regulations.

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Xiong, Z., Sneiderman, C.T., Kuminkoski, C.R. et al. Transcript-targeted antigen mapping reveals the potential of POSTN splicing junction epitopes in glioblastoma immunotherapy. Genes Immun 26, 190–199 (2025). https://doi.org/10.1038/s41435-025-00326-6

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