Leen Ann M, Sukumaran Sujita, Watanabe Norihiro, Mohammed Somala, Keirnan Jacqueline, Yanagisawa Ryu, Anurathapan Usanarat, Rendon David, Heslop Helen E, Rooney Cliona M, Brenner Malcolm K, Vera Juan F
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
Mol Ther. 2014 Jun;22(6):1211-1220. doi: 10.1038/mt.2014.47. Epub 2014 Mar 20.
The success of adoptively transferred tumor-directed T cells requires them to survive and expand in vivo. Most tumors, however, employ immune evasion mechanisms, including the production of inhibitory cytokines that limit in vivo T-cell persistence and effector function. To protect tumor-directed T cells from such negative influences, we generated a chimeric cytokine receptor in which the interleukin (IL) 4 receptor exodomain was fused to the IL7 receptor endodomain. We thereby inverted the effects of tumor-derived IL4 so that the proliferation and activation of tumor directed cytotoxic T cells was enhanced rather than inhibited in the tumor microenvironment, resulting in superior antitumor activity. These transgenic T cells were only activated in the tumor environment since triggering required exposure to both tumor antigen (signal 1) and tumor-derived IL4 (signal 2). This selectivity supports future clinical adaptation.
过继转移的肿瘤定向T细胞的成功需要它们在体内存活并扩增。然而，大多数肿瘤采用免疫逃避机制，包括产生抑制性细胞因子，这些因子会限制体内T细胞的持久性和效应功能。为了保护肿瘤定向T细胞免受此类负面影响，我们构建了一种嵌合细胞因子受体，其中白细胞介素（IL）4受体胞外结构域与IL7受体胞内结构域融合。我们由此逆转了肿瘤衍生IL4的作用，使得肿瘤定向细胞毒性T细胞在肿瘤微环境中的增殖和激活得到增强而非抑制，从而产生了卓越的抗肿瘤活性。这些转基因T细胞仅在肿瘤环境中被激活，因为激活需要同时暴露于肿瘤抗原（信号1）和肿瘤衍生的IL4（信号2）。这种选择性为未来的临床应用提供了支持。
