Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity
Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity
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DOI：
10.1172/jci66301
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发表时间：
2013-06-01
影响因子：
15.9
通讯作者：
van den Brink, Marcel R. M.
中科院分区：
文献类型：
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作者：
Ghosh, Arnab;Dogan, Yildirim;van den Brink, Marcel R. M.
目前抑制移植物抗宿主病（GVHD）的策略也会损害移植物抗肿瘤（GVT）反应。此外，大多数分离 GVHD 和 GVT 反应的实验策略只是保留 GVT 功能，而没有真正增强它。我们之前已经证明内源性表达TNF相关的凋亡诱导配体。 (TRAIL) 是同种异体造血干细胞移植 (allo-HSCT) 受者针对某些恶性肿瘤的最佳 GVT 活性所必需的。为了模拟供体来源的细胞疗法，我们对 T 细胞进行基因工程改造，使其过表达 TRAIL，并将供体型未分选的 TRAIL(+) T 细胞过继转移到同种异体造血干细胞移植的小鼠模型中。我们发现小鼠TRAIL(+) T细胞诱导同种异体反应性T细胞凋亡，从而以DR5依赖性方式减少GVHD。此外，小鼠TRAIL(+) T细胞介导增强的体外和体内抗淋巴瘤GVT反应。此外，人TRAIL(+) T细胞介导增强的针对人白血病细胞系和新分离的慢性淋巴细胞白血病(CLL)细胞的体外细胞毒性。最后，作为现成的、不受供体限制的抗肿瘤细胞治疗的模型，来自第三方供体的体外产生的 TRAIL(+) 前体 T 细胞在没有 GVHD 的情况下也介导了增强的 GVT 反应。这些数据表明，TRAIL 过表达的供体 T 细胞可能通过增加 GVT 反应和抑制 GVHD 来增强异基因 HSCT 的治疗潜力。
Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand. (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL(+) T cells into mouse models of allo-HSCT. We found that murine TRAIL(+) T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL(+) T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL(+) T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro-generated TRAIL(+) precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD.