肿瘤细胞治疗研究
英文原题：C/EBPβ-induced alternative splicing of RCAN1 generates a potent TCR-T target in mesenchymal glioblastoma.
胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，治疗选择有限，预后极差。
胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，治疗方案有限且预后极差。尽管免疫疗法在治疗某些实体瘤方面显示出前景，但由于缺乏可靶向的肿瘤抗原以及高度的肿瘤异质性，GBM的治疗大多未能成功。在此，我们报道RCAN1-4是一种由转录因子C/EBP诱导的可变剪接产生的新型肿瘤抗原。C/EBP和RCAN1-4作为间充质亚型的标志，在GBM和胶质瘤干细胞中均高表达。我们报道了一个位于外显子4和外显子5之间、为RCAN1-4所特有的免疫原性HLA-A24特异性剪接接头表位。该表位在HLA-A24+供者和GBM患者中刺激T细胞应答的能力得到了验证，这使我们得以鉴定出RCAN1-4反应性T细胞受体（TCR），用于构建TCR工程化T细胞（TCR-T细胞）。TCR-T的功能研究证明其可在体外和体内杀伤RCAN1-4阳性GBM肿瘤细胞，凸显了其作为间充质型GBM免疫治疗靶点的潜力。
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/EBP . Both C/EBP 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 RCAN1-4 pos GBM tumor cells, highlighting its potential as an immunotherapeutic target in mesenchymal GBM.
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