Intralesional delivery of dendritic cells engineered to express T-bet promotes protective type 1 immunity and the normalization of the tumor microenvironment.
Intralesional delivery of dendritic cells engineered to express T-bet promotes protective type 1 immunity and the normalization of the tumor microenvironment.
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DOI：
10.4049/jimmunol.1001294
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发表时间：
2010-09-01
期刊：
影响因子：
--
通讯作者：
Storkus WJ
中科院分区：
文献类型：
--
作者：
Qu Y;Chen L;Pardee AD;Taylor JL;Wesa AK;Storkus WJ
T-bet (Tbx21) 是一种 T-box 转录因子，之前已被确定为 1 型 T 细胞极化的主要调节因子。我们最近还表明，表达 hT-bet cDNA 的人类 DC 基因工程在体外产生了 1 型极化 APC。在当前的研究中，用编码全长 mT-bet (DC.mTbet) 的重组腺病毒转导小鼠 CD11c+ DC，并分析其体外和体内免疫调节功能。在分析的标记范围内，DC.mTbet 表现出对照 DC 表型，并且在体外混合淋巴细胞反应中促进同种异体 T 细胞增殖的能力与对照 DC 没有区别。然而，DC.mTbet 在体外促进 Th1 和 Tc1 反应方面优于对照 DC，这是通过一种需要 DC-T 细胞相互作用或这两种细胞类型非常接近的机制实现的，这只能部分地通过 DC 精心设计的 IL-12p70 的作用来解释。皮下注射第 7 天时在同源 Balb/c 小鼠中生长的 CMS4 肉瘤病变，DC.mTbet 通过依赖 CD4+ 和 CD8+ T 细胞以及较小程度上依赖 asialoGM1+ NK 细胞的机制，显着减缓了肿瘤进展（与对照 DC 相比）并延长了总体生存期。基于 DC.mTbet 的治疗还促进了治疗动物的脾脏和肿瘤引流淋巴结 (TDLN) 中优异的肿瘤特异性 Tc1 反应，并且在肿瘤微环境中，它抑制了 CD11b+Gr1+ 骨髓源性抑制细胞 (MDSC) 的积累并使 CD31+ 血管结构正常化。这些发现支持 DC.Tbet 作为癌症治疗方式的潜在转化效用。
T-bet (Tbx21), a T-box transcription factor, has been previously identified as a master regulator of Type-1 T cell polarization. We have also recently shown that the genetic engineering of human DC to express hT-bet cDNA yields a Type-1 polarizing APC in vitro. In the current study, murine CD11c+ DCs were transduced with a recombinant adenovirus encoding full-length mT-bet (DC.mTbet) and analyzed for their immunomodulatory functions in vitro and in vivo. Within the range of markers analyzed, DC.mTbet exhibited a control DC phenotype and were indistinguishable from control DC in their ability to promote allogenic T cell proliferation in mixed lymphocyte reactions in vitro. However, DC.mTbet were superior to control DC in promoting Th1 and Tc1 responses in vitro, via a mechanism requiring DC-T cell interaction or the close proximity of these 2 cell types and which can only partially be explained by the action of DC elaborated IL-12p70. When injected into day 7 s.c. CMS4 sarcoma lesions growing in syngenic Balb/c mice, DC.mTbet dramatically slowed tumor progression (versus control DC) and extended overall survival via a mechanism dependent on both CD4+ and CD8+ T cells, and to a lesser extent, asialoGM1+ NK cells. DC.mTbet-based therapy also promoted superior tumor-specific Tc1 responses in the spleens and tumor-draining lymph nodes (TDLN) of treated animals, and within the tumor microenvironment, it inhibited the accumulation of CD11b+Gr1+ myeloid-derived suppressor cells (MDSC) and normalized CD31+ vascular structures. These findings support the potential translational utility of DC.Tbet as a therapeutic modality in the cancer setting.
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影响因子：
11.2
作者：
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通讯作者：
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