肿瘤细胞治疗研究
英文原题：Novel CAR-T Cells Specifically Targeting SIA-CIgG Demonstrate Effective Antitumor Efficacy in Bladder Cancer.
嵌合抗原受体（CAR）T 细胞疗法是一种有前景的癌症治疗方法。
嵌合抗原受体（CAR）T细胞疗法是一种有前景的癌症治疗方法。然而，其在膀胱癌（BC）中的应用仍然有限，部分原因是缺乏合适的靶分子。唾液酸化的癌源性IgG（SIA-CIgG）在BC中高表达，并与恶性生物学行为密切相关。然而，其作为CAR-T细胞疗法治疗BC靶点的潜力尚未确定。本研究发现，SIA-CIgG在大多数BC样本中高表达，但在正常组织中表达有限。特异性靶向SIA-CIgG的CAR-T细胞能够有效裂解BC细胞，且其细胞毒性依赖于SIA-CIgG表达。此外，与已进行广泛临床试验的人表皮生长因子受体2（HER2）CAR-T细胞相比，SIA-CIgG CAR-T细胞表现出更温和的肿瘤细胞裂解和更强的持久性。在反复受到肿瘤抗原刺激后，SIA-CIgG CAR-T细胞在转录组和染色质可及性方面均显示出显著改变。当将SIA-CIgG CAR-T细胞疗法与FDA批准用于治疗BC的药物联合使用时，发现组蛋白去乙酰化酶抑制剂（HDACi）vorinostat可增强CAR-T细胞裂解肿瘤细胞的能力。因此，SIA-CIgG CAR-T细胞与vorinostat的联合方案在BC治疗中具有前景。
Chimeric Antigen Receptor (CAR) T-cell therapy is a promising cancer treatment method. However, its application in bladder cancer (BC) remains limited, partially because of the absence of appropriate target molecules. Sialylated cancer-derived IgG (SIA-CIgG) is highly expressed in BC and is closely associated with malignant biological behavior. However, its potential as a target for CAR-T cell therapy to treat BC is yet to be established. Here, it is found that SIA-CIgG is highly expressed in most BC samples but displayed limited expression in normal tissues. CAR-T cells specifically targeting SIA-CIgG can effectively lyse BC cells and the cytotoxicity depends on SIA-CIgG expression. Furthermore, SIA-CIgG CAR-T cells demonstrate milder tumor cell lysis and enhanced persistence compared with human epidermal growth factor receptor 2 (HER2) CAR-T cells, which have undergone extensive clinical trials. After repeated tumor antigen challenges, SIA-CIgG CAR-T cells display substantial alterations in both the transcriptome and chromatin accessibility. When combining SIA-CIgG CAR-T cell therapy with FDA-approved drugs to treat BC, the histone deacetylase inhibitor (HDACi), vorinostat, is found to enhance the ablility of CAR-T cells for tumor cell lysis. Therefore, the combination of SIA-CIgG CAR-T cells and vorinostat is promising for BC treatment.
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