Development of a Listeria monocytogenes-based vaccine against hepatocellular carcinoma
Development of a Listeria monocytogenes-based vaccine against hepatocellular carcinoma
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开发基于单核细胞增生李斯特氏菌的肝细胞癌疫苗
DOI：
10.1038/onc.2011.395
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发表时间：
2012-04-01
期刊：
影响因子：
8
通讯作者：
Sun, B.
中科院分区：
文献类型：
--
作者：
Chen, Y.;Yang, D.;Sun, B.
减毒活单核细胞增生李斯特菌（LM）是一种很有前途的细菌载体，能够诱导T细胞对肿瘤相关抗原的反应，并在疫苗开发中显示出巨大的潜力。一种新的基于LM的重组疫苗（Lmdd（LM Delta dal Delta dat）-MPFG（多肽融合基因））被开发为具有表达和分泌肝细胞癌（HCC）相关的肿瘤相关抗原片段的能力，这是由于插入了肝炎B病毒（HBV）-X蛋白（HBx）衍生的表位HBx（52-60）和HBx（140-148），通用的T辅助表位，甲胎蛋白（AFP）表位AFP（158-166）和黑色素瘤抗原基因（法师）-3（271 -279）插入HBV核心蛋白。在用Lmdd-MPFG疫苗免疫后，巨噬细胞表现出细菌摄取;然后在第一次施用后3天疫苗几乎被清除。在随后的疫苗接种后，它消失得更快。然而，重组Lmdd-MPFG允许针对MPFG的人白细胞抗原（HLA）-A0201表位的抗肿瘤应答的充分发展。每个表位刺激增强的T细胞增殖，并在体外提高干扰素（IFN）-γ的上清液水平。此外，在HLA-A2转基因小鼠中，产生IFN-γ的CD 8（+）T细胞以及体内细胞溶解活性显著增加。此外，Lmdd-MPFG产生了强烈的抗肿瘤反应，如免疫小鼠在预防和治疗环境中对MPFG阳性Hepa 1 -6细胞攻击的显著抗性所示。肿瘤消退伴随着增强的细胞毒性T淋巴细胞反应和肿瘤中调节性T细胞的减少。总的来说，这些结果表明，利用减毒LM作为疫苗载体，能够携带MPFG基因，提出了一个潜在的可行的策略，用于预防肝癌。Oncogene（2012）31，2140-2152; doi：10.1038/onc.2011.395; 2011年9月19日在线发表
Live attenuated Listeria monocytogenes (LM) is a promising bacterial vector able to induce a T-cell response to tumor-associated antigens and demonstrates great potential for use in vaccine development. A novel recombinant LM-based vaccine (Lmdd (LM Delta dal Delta dat)-MPFG (multiple peptide fusing genes)) was developed with the ability to express and secrete hepatocellular carcinoma (HCC)-related tumor-associated antigens fragments due to the insertion of hepatitis B virus (HBV)-X protein (HBx)-derived epitopes HBx(52-60) and HBx(140-148), the universal T-helper epitope, alpha-fetoprotein (AFP) epitope AFP(158-166), and melanoma antigen gene (MAGE)-3(271-279) into the HBV core protein. Following immunization with the Lmdd-MPFG vaccine, macrophages exhibited uptake of the bacteria; the vaccine was then nearly cleared 3 days after the first administration. It disappeared even more quickly following subsequent vaccinations. However, recombinant Lmdd-MPFG allowed for the full development of an antitumor response towards the human leukocyte antigen (HLA)-A0201 epitopes of MPFG. Each epitope stimulated an augmented T-cell proliferation and enhanced the supernatant level of interferon (IFN)-gamma in vitro. In addition, IFN-gamma-producing CD8(+) T cells as well as in vivo cytolytic activity were significantly increased in HLA-A2 transgenic mice. Additionally, the Lmdd-MPFG developed a strong antitumor response, as indicated by the significant resistance of immunized mice to MPFG-positive Hepa1-6 cell challenge in both a prophylactic and therapeutic setting. Tumor regression was accompanied by an enhanced cytotoxic T lymphocyte response and a decrease of regulatory T cells in the tumor. Collectively, these results suggest that utilizing attenuated LM as a vaccine vector, able to carry the MPFG gene, presents a potentially feasible strategy for prevention of HCC. Oncogene (2012) 31, 2140-2152; doi:10.1038/onc.2011.395; published online 19 September 2011