Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
J Immunol. 2013 Sep 15;191(6):3232-9. doi: 10.4049/jimmunol.1301270. Epub 2013 Aug 12.
TCR gene therapy is a promising approach for the treatment of various human malignancies. However, the tumoricidal activity of TCR-modified T cells may be limited by local immunosuppressive mechanisms within the tumor environment. In particular, many malignancies induce T cell suppression in their microenvironment by TGF-β secretion. In this study, we evaluate whether blockade of TGF-β signaling in TCR-modified T cells enhances TCR gene therapy efficacy in an autochthonous mouse tumor model. Treatment of mice with advanced prostate cancer with T cells genetically engineered to express a tumor-reactive TCR and a dominant-negative TGF-β receptor II induces complete and sustained tumor regression, enhances survival, and leads to restored differentiation of prostate epithelium. These data demonstrate the potential to tailor the activity of TCR-modified T cells by additional genetic modification and provide a strong rationale for the clinical testing of TGF-β signaling blockade to enhance TCR gene therapy against advanced cancers.
T 细胞受体基因治疗是治疗各种人类恶性肿瘤的一种有前途的方法。然而，T 细胞受体修饰的 T 细胞的细胞毒性活性可能受到肿瘤微环境中局部免疫抑制机制的限制。特别是，许多恶性肿瘤通过 TGF-β 的分泌在其微环境中诱导 T 细胞抑制。在这项研究中，我们评估了在 TCR 修饰的 T 细胞中阻断 TGF-β 信号是否会增强 TCR 基因治疗在同源小鼠肿瘤模型中的疗效。用遗传工程表达肿瘤反应性 TCR 和显性失活 TGF-β 受体 II 的 T 细胞治疗患有晚期前列腺癌的小鼠，可诱导完全和持续的肿瘤消退，提高生存率，并导致前列腺上皮的分化恢复。这些数据证明了通过额外的基因修饰来调整 TCR 修饰的 T 细胞活性的潜力，并为临床测试 TGF-β 信号阻断以增强针对晚期癌症的 TCR 基因治疗提供了强有力的依据。
