Objective: Cancer stem cell is one of the important causes of tumorigenesis as well as a drug target in the treatment of malignant tumor. However, at present, there is no immune vaccine targeting these cells. Octamer-binding transcription factor 4 (OCT4), a marker of embryonic stem cells and germ cells, often highly expresses in the early stages of tumorigenesis and is therefore a good candidate for cancer vaccine development. Methods: To identify the optimal carrier and adjuvant combination, we chemically synthesized and linked three different OCT4 epitope antigens to a carrier protein, keyhole limpet hemocyanin (KLH), combined with Toll-like receptor 9 agonist (TLR9). Results: Immunization with OCT4-3 + TLR9 produced the strongest immune response in mice. In prevention assays, significant tumor growth inhibition was achieved in BABL/c mice treated with OCT4-3 + TLR9 (P < 0.01). Importantly, the results showed that cytotoxic T lymphocyte activity and the inhibition of tumor growth were enhanced in mice immunized with OCT4-3 combined with TLR9. Meanwhile, multiple cytokines [such as interferon (IFN)-γ (P < 0.05), interleukin (IL)-12 (P < 0.05), IL-2 (P < 0.01), and IL-6 (P < 0.05)] promoting cellular immune responses were shown to be greatly enhanced in mice immunized with OCT4-3 + TLR9. Moreover, we considered safety considerations in terms of the composition of the vaccines to help facilitate the development of effective next-generation vaccines. Conclusions: Collectively, these experiments demonstrated that combination therapy with TLR9 agonist induced a tumor-specific adaptive immune response, leading to the suppression of primary tumor growth in testis embryonic carcinoma.

译文

目的: 肿瘤干细胞是肿瘤发生的重要原因之一,也是治疗恶性肿瘤的药物靶点。但是,目前还没有针对这些细胞的免疫疫苗。八聚体结合转录因子4 (OCT4) 是胚胎干细胞和生殖细胞的标志物,通常在肿瘤发生的早期阶段高度表达,因此是癌症疫苗开发的良好候选者。方法: 为了确定最佳的载体和佐剂组合,我们化学合成了三种不同的OCT4表位抗原,并将其与载体蛋白匙孔血蓝蛋白 (KLH) 和Toll样受体9激动剂 (TLR9) 结合。结果: OCT4-3 + TLR9预防接种小鼠免疫反应最强。在预防试验中,在用OCT4-3 + TLR9处理的BABL/c小鼠中实现了显著的肿瘤生长抑制 (P <0.01)。重要的是,结果表明,OCT4-3联合tlr9免疫小鼠的细胞毒性T淋巴细胞活性和对肿瘤生长的抑制作用增强。同时,多种细胞因子 [干扰素 (IFN)-γ (P <0.05),白细胞介素 (IL)-12 (P <0.05),IL-2 (P <0.01),并且IL-6 (P < 0.05)] 促进细胞免疫应答在用OCT4-3 + tlr9免疫的小鼠中显示出显著增强。此外,我们考虑了疫苗组成方面的安全性考虑,以帮助促进有效的下一代疫苗的开发。结论: 总的来说,这些实验表明,与TLR9激动剂联合治疗可诱导肿瘤特异性适应性免疫反应,从而抑制睾丸胚胎癌的原发性肿瘤生长。

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