Blockade of TGF-β Signaling Greatly Enhances the Efficacy of TCR Gene Therapy of Cancer
Blockade of TGF-β Signaling Greatly Enhances the Efficacy of TCR Gene Therapy of Cancer
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DOI：
10.4049/jimmunol.1301270
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发表时间：
2013-09-15
影响因子：
4.4
通讯作者：
Schumacher, Ton N. M.
中科院分区：
文献类型：
--
作者：
Bendle, Gavin M.;Linnemann, Carsten;Schumacher, Ton N. M.
TCR基因疗法是治疗各种人类恶性肿瘤的一种有前途的方法。然而，TCR修饰的T细胞的杀肿瘤活性可能受到肿瘤环境内局部免疫抑制机制的限制。特别是，许多恶性肿瘤通过 TGF-β 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 TCR 修饰 T 细胞中 TGF-β 信号传导的阻断是否可以增强本地小鼠肿瘤模型中的 TCR 基因治疗效果。使用基因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，可诱导肿瘤完全且持续消退，提高存活率，并恢复前列腺上皮的分化。这些数据证明了通过额外的基因修饰来定制 TCR 修饰的 T 细胞活性的潜力，并为 TGF-β 信号传导阻断的临床测试提供了强有力的理论依据，以增强针对晚期癌症的 TCR 基因治疗。
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-beta secretion. In this study, we evaluate whether blockade of TGF-beta 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-beta 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-beta signaling blockade to enhance TCR gene therapy against advanced cancers.