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<p>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<sup>+</sup> 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 RCAN1-4<sup>pos</sup> GBM tumor cells, highlighting its potential as an immunotherapeutic target in mesenchymal GBM.</p>

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C/EBPβ-induced alternative splicing of RCAN1 generates a potent TCR-T target in mesenchymal glioblastoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月23日

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  • Zujian Xiong,
  • Qinglin Kong,
  • Bhuvitha Chagantipati,
  • Amelia Stepniak,
  • Ambika P. Jaswal,
  • Chaim T. Sneiderman,
  • Yuanyuan Han,
  • Sydney A. Jackson,
  • Rebecca A. Raphael,
  • Wei Zhang,
  • Muzi Li,
  • Yapeng Chao,
  • Bin Qin,
  • Zeynep Dulkadir,
  • Lance Schwegman,
  • Yihao Zhang,
  • Chloe Kuminkoski,
  • Megan A. Mahlke,
  • Poulomi Nath,
  • Baoli Hu,
  • Pascal O. Zinn,
  • Megan Mantica,
  • Sameer Agnihotri,
  • Yael Nechemia-Arbely,
  • Ian F. Pollack,
  • Lora H. Rigatti,
  • Thomas G. Forsthuber,
  • Xuejun Li,
  • Itay Raphael,
  • Gary Kohanbash

摘要

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.