Targeting Stat3 in the myeloid compartment drastically improves the in vivo antitumor functions of adoptively transferred T cells.
Targeting Stat3 in the myeloid compartment drastically improves the in vivo antitumor functions of adoptively transferred T cells.
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DOI：
10.1158/0008-5472.can-10-0736
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发表时间：
2010-10-01
期刊：
影响因子：
11.2
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Herrmann A;Kortylewski M;Kujawski M;Zhang C;Reckamp K;Armstrong B;Wang L;Kowolik C;Deng J;Figlin R;Yu H
改善效应T细胞功能是预防或治疗多种疾病的重要手段。髓系间室Stat3抑制Th-1型免疫，抑制自然和诱导的抗肿瘤免疫反应。我们最近开发了一种体内siRNA递送平台，通过将TLR9激动剂与siRNA偶联，有效靶向髓细胞和B细胞。在这里，我们发现无论是消融髓系室和B细胞中的Stat3等位基因，结合CpG触发或给药CpG- stat3sirna偶联物，都极大地增强了过继转移CD8+ T细胞的效应功能。具体来说，我们证明这两种方法都能够增加肿瘤引流淋巴结中的树突状细胞和CD8+ T细胞的参与。此外，这两种方法都能在体内显著激活转移的CD8+ T细胞，上调穿孔蛋白、颗粒酶B和IFN-γ等效应分子。活体多光子显微镜显示Stat3沉默联合CpG触发大大增加了转移T细胞的杀伤活性和肿瘤浸润。这些结果表明，CpG-Stat3siRNA和其他Stat3抑制剂可能是一种有效的辅助剂，可以改善T细胞治疗。
Improving effector T cell functions is highly desirable for preventive or therapeutic interventions of diverse diseases. Stat3 in the myeloid compartment constrains Th-1 type immunity, dampening natural and induced antitumor immune responses. We have recently developed an in vivo siRNA delivery platform by conjugating a TLR9 agonist with siRNA that efficiently targets myeloid and B cells. Here we show that either ablating the Stat3 alleles in the myeloid compartment and B cells combined with CpG triggering or administrating the CpG-Stat3siRNA conjugates drastically augments effector functions of adoptively transferred CD8+ T cells. Specifically, we demonstrate that both approaches are capable of increasing dendritic cell and CD8+ T cell engagement in tumor draining lymph nodes. Furthermore, both approaches can significantly activate the transferred CD8+ T cells in vivo, upregulating effector molecules such as perforin, granzyme B and IFN-γ. Intravital multiphoton microscopy reveals that Stat3 silencing combined with CpG triggering greatly increases killing activity and tumor infiltration of transferred T cells. These results suggest the use of CpG-Stat3siRNA, and possibly other Stat3 inhibitors, as a potent adjuvant to improve T cell therapies.