In Vivo Programming of Tumor Antigen-Specific T Lymphocytes from Pluripotent Stem Cells to Promote Cancer Immunosurveillance
In Vivo Programming of Tumor Antigen-Specific T Lymphocytes from Pluripotent Stem Cells to Promote Cancer Immunosurveillance
复制标题
DOI：
10.1158/0008-5472.can-11-0359
复制
发表时间：
2011-07-15
期刊：
影响因子：
11.2
通讯作者：
Song, Jianxun
中科院分区：
文献类型：
--
作者：
Lei, Fengyang;Zhao, Baohua;Song, Jianxun
连续性T细胞免疫疗法已经引起了广泛的关注，但其有效使用受到需要复杂且昂贵的多次离体操作和输注的限制。在这项研究中，我们展示了如何从诱导多能干细胞（iPS）中产生高反应性抗原（Ag）特异性CTL，为过继免疫治疗提供无限的功能性CTL来源。iPS细胞衍生的T细胞可以提供避免可能的免疫排斥反应和规避与其他干细胞类型相关的伦理和实际问题的优势。iPS细胞可以通过在骨髓基质细胞上过表达的Notch配体Delta-like 1（DL 1）刺激在体外分化为祖T细胞，在过继转移到Rag 1缺陷小鼠中后发生完全成熟。在这里，我们报告说，这些iPS细胞可以在体内分化成功能性CTL后，过表达的MHC I限制性Ag特异性T细胞受体（TCR）。在这项研究中，我们通过逆转录病毒介导的转导产生了用卵清蛋白（OVA）特异性和MHC-I限制性TCR（OT-I）遗传修饰的小鼠iPS细胞。在将其过继转移到受体小鼠中后，大多数OT-I/iPS细胞经历分化为CD 8（+）CTL。体内开发的TCR转导的iPS细胞通过分泌白细胞介素2和IFN-γ在体外对肽刺激作出反应。最重要的是，TCR转导的iPS细胞的过继转移触发了OVA反应性CTL向肿瘤组织中的浸润，并保护动物免受肿瘤攻击。综上所述，我们的研究结果提供了一种可能更有效的方法来产生Ag特异性T淋巴细胞用于过继免疫治疗的概念证明。Cancer Res; 71（14）; 4742-7. (C)2011年AACR。
Adoptive T-cell immunotherapy has garnered wide attention, but its effective use is limited by the need of multiple ex vivo manipulations and infusions that are complex and expensive. In this study, we show how highly reactive antigen (Ag)-specific CTLs can be generated from induced pluripotent stem (iPS) cells to provide an unlimited source of functional CTLs for adoptive immunotherapy. iPS cell-derived T cells can offer the advantages of avoiding possible immune rejection and circumventing ethical and practical issues associated with other stem cell types. iPS cells can be differentiated into progenitor T cells in vitro by stimulation with the Notch ligand Delta-like 1 (DL1) overexpressed on bone marrow stromal cells, with complete maturation occurring upon adoptive transfer into Rag1-deficient mice. Here, we report that these iPS cells can be differentiated in vivo into functional CTLs after overexpression of MHC I-restricted Ag-specific T-cell receptors (TCR). In this study, we generated murine iPS cells genetically modified with ovalbumin (OVA)-specific and MHC-I restricted TCR (OT-I) by retrovirus-mediated transduction. After their adoptive transfer into recipient mice, the majority of OT-I/iPS cells underwent differentiation into CD8(+) CTLs. TCR-transduced iPS cells developed in vivo responded in vitro to peptide stimulation by secreting interleukin 2 and IFN-gamma. Most importantly, adoptive transfer of TCR-transduced iPS cells triggered infiltration of OVA-reactive CTLs into tumor tissues and protected animals from tumor challenge. Taken together, our findings offer proof of concept for a potentially more efficient approach to generate Ag-specific T lymphocytes for adoptive immunotherapy. Cancer Res; 71(14); 4742-7. (C) 2011 AACR.