Protective Cancer Vaccine Using Genetically Modified Hematopoietic Stem Cells.
Protective Cancer Vaccine Using Genetically Modified Hematopoietic Stem Cells.
复制标题
DOI：
10.3390/vaccines6030040
复制
发表时间：
2018-07-06
期刊：
影响因子：
7.8
通讯作者：
Song J
中科院分区：
文献类型：
--
作者：
Xiong X;Das JK;Song J;Ni B;Ren X;Yang JM;Song J
造血干细胞（HSCs）可产生血细胞的髓系和淋巴系谱系，并且能够被重编程为肿瘤抗原（Ag）特异性的CD8 + 细胞毒性T淋巴细胞（CTLs）以阻止肿瘤生长。然而，从造血干细胞分化出肿瘤抗原特异性CTLs（如HSC - CTLs）的最佳方法仍然不清楚。在当前的研究中，我们表明造血干细胞的基因修饰与体内T细胞发育相结合有助于产生抑制肿瘤生长的抗原特异性CTLs。用鸡卵清蛋白（OVA）特异性T细胞受体进行基因修饰的小鼠造血干细胞被过继转移到受体小鼠体内。在接下来的一周内，给小鼠腹腔注射激动剂α - Notch 2抗体和细胞因子（rFlt3L和rIL - 7）三次。又过了两周后，在对源自造血干细胞的T细胞的抗肿瘤活性进行评估之前，给小鼠皮下接种表达OVA作为替代肿瘤抗原的B16 - OVA黑色素瘤细胞。OVA特异性CTLs在体内发育，并在体外对OVA抗原刺激有强烈反应。此外，接受基因修饰的造血干细胞并在体内引发免疫反应的小鼠建立了抗肿瘤免疫，从而抑制了肿瘤生长。本研究报告的这些结果为利用基因修饰的造血干细胞开发保护性癌症疫苗提供了一种替代策略。
Hematopoietic stem cells (HSCs) yield both the myeloid and lymphoid lineages of blood cells and can be reprogrammed into tumor antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) to prevent tumor growth. However, the optimal approach for differentiating tumor Ag-specific CTLs from HSCs, such as HSC-CTLs, remains elusive. In the current study, we showed that a combination of genetic modification of HSCs and in vivo T cell development facilitates the generation of Ag-specific CTLs that suppressed tumor growth. Murine HSCs, which were genetically modified with chicken ovalbumin (OVA)-specific T cell receptor, were adoptively transferred into recipient mice. In the following week, mice were administered with intraperitoneal injections of an agonist α-Notch 2 antibody and cytokines (rFlt3L and rIL-7) three times. After another two weeks, mice received a subcutaneous inoculation of B16-OVA melanoma cells that express OVA as a surrogate tumor Ag, before the anti-tumor activity of HSC-derived T cells was assessed. OVA-specific CTLs developed in vivo and greatly responded to OVA Ag stimulation ex vivo. In addition, mice receiving genetically modified HSCs and in vivo priming established anti-tumor immunity, resulting in the suppression of tumor growth. These results reported in this present study provide an alternative strategy to develop protective cancer vaccines by using genetically modified HSCs.