de Rooij Marije A J, Meeuwsen Miranda H, Wouters Anne K, Remst Dennis F G, Hagedoorn Renate S, van der Steen Dirk M, Verdegaal Els M E, Wachsmann Tassilo L A, Falkenburg J H Frederik, Heemskerk Mirjam H M
Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands.
Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden 2333ZA, the Netherlands.
Mol Ther Oncol. 2025 Jul 17;33(3):201018. doi: 10.1016/j.omton.2025.201018. eCollection 2025 Sep 18.
Cancer testis antigens (CTAs) can be expressed in tumors, whereas expression is silenced in normal tissue except for the immune-privileged testis. This quasi-tumor-restricted expression makes CTAs attractive targets for T cell receptor (TCR) gene therapy. However, CTA-specific TCR gene therapy is only applicable for tumors with substantial and homogeneous CTA expression. To increase the number of patients eligible for CTA-specific TCR gene therapy, CTA expression can be upregulated with DNA-demethylating agents like 5-aza-2'-deoxycytidine (DAC). Here, we studied the effect of DAC on the recognition of a wide range of tumor cells by TCR-engineered T cells specific for the CTAs MAGE-A1, MAGE-A3/A6, or MAGE-A9. DAC treatment strongly increased expression in most tumor cell lines tested and strongly induced or improved recognition by MAGE-specific TCR-engineered T cells. However, upregulation was not limited to tumor cells but also occurred in healthy cells, resulting in MAGE-specific T cell reactivity against proliferating T and B cells. Overall, these results underscore the potential of DAC treatment to induce expression in tumor cells and to increase their sensitivity for MAGE-specific T cell therapy. However, DAC treatment can potentially result in on-target off-tumor reactivity, warranting careful consideration when using DAC as sensitizing strategy prior to adoptive transfer of CTA-specific T cells.
癌睾丸抗原（CTA）可在肿瘤中表达，而在除免疫豁免器官睾丸外的正常组织中其表达被沉默。这种近乎肿瘤限制性的表达使得CTA成为T细胞受体（TCR）基因治疗有吸引力的靶点。然而，CTA特异性TCR基因治疗仅适用于CTA表达大量且均匀的肿瘤。为了增加符合CTA特异性TCR基因治疗条件的患者数量，可用5-氮杂-2'-脱氧胞苷（DAC）等DNA去甲基化剂上调CTA表达。在此，我们研究了DAC对MAGE-A1、MAGE-A3/A6或MAGE-A9等CTA特异性TCR工程化T细胞识别多种肿瘤细胞的影响。DAC处理在大多数测试的肿瘤细胞系中强烈增加了 表达，并强烈诱导或改善了MAGE特异性TCR工程化T细胞的识别。然而， 上调不仅限于肿瘤细胞，也发生在健康细胞中，导致MAGE特异性T细胞对增殖的T细胞和B细胞产生反应。总体而言，这些结果强调了DAC处理在诱导肿瘤细胞中 表达以及增加其对MAGE特异性T细胞治疗敏感性方面的潜力。然而，DAC处理可能会导致靶向脱肿瘤反应，在将CTA特异性T细胞过继转移之前将DAC用作致敏策略时需要仔细考虑。
