Multiple Antigenic Peptides Based on H-2Kb–Restricted CTL Epitopes from Murine Heparanase Induce a Potent Antitumor Immune Response In Vivo
Multiple Antigenic Peptides Based on H-2Kb–Restricted CTL Epitopes from Murine Heparanase Induce a Potent Antitumor Immune Response In Vivo
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DOI：
10.1158/1535-7163.mct-11-0607
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发表时间：
2012-03
影响因子：
5.7
通讯作者：
Xu-dong Tang;Guo-Zhen Wang;Jun-Gu Guo;Mu-Han Lü;Chuan Li;Ning Li;Ya-Ling Chao;Chang-Zhu Li;Yu-yun Wu;Chang-jiang Hu;D. Fang;Shi-ming Yang
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文献类型：
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作者：
Xu-dong Tang;Guo-Zhen Wang;Jun-Gu Guo;Mu-Han Lü;Chuan Li;Ning Li;Ya-Ling Chao;Chang-Zhu Li;Yu-yun Wu;Chang-jiang Hu;D. Fang;Shi-ming Yang
越来越多的研究表明乙酰肝素酶可能是一种通用的肿瘤相关抗原（TAA）。人类和小鼠的几种乙酰肝素酶 T 细胞表位已被鉴定。然而，由于免疫原性低，多肽疫苗通常难以在体内诱导有效的抗肿瘤免疫反应。在本研究中，为了提高多肽疫苗的免疫原性，我们基于小鼠乙酰肝素酶（mHpa）T细胞表位（mHpa398和mHpa519）设计并合成了两种四分支多抗原肽（MAP）。来自小鼠骨髓的树突状细胞（DC）负载有来自乙酰肝素酶的上述MAP疫苗，用于评估针对各种肿瘤细胞系的免疫反应，并与对其相应线性肽的免疫反应进行比较，体外和体内。我们进一步评估了 CD4+ T 细胞耗尽和非耗尽小鼠中 IFN-γ 的释放。结果表明，与接种相应线性肽的小鼠产生的效应器相比，由负载有 MAP 疫苗接种的小鼠脾细胞的 DC 产生的效应器诱导针对同时表达乙酰肝素酶和 H-2Kb 的靶细胞的更强的免疫反应。 MAP 和线性肽疫苗接种诱导的乙酰肝素酶特异性 CD8+ T 细胞反应需要 CD4+ T 细胞的协同作用。此外，乙酰肝素衍生的MAP疫苗显着抑制C57BL/6小鼠中B16鼠黑色素瘤的生长，同时还提高了荷瘤小鼠的存活率。我们的数据表明，基于乙酰肝素酶 T 细胞表位的 MAP 疫苗是肿瘤免疫治疗的有效免疫原。摩尔癌症治疗； 11(5)； 1183–92。 ©2012 AACR。
Accumulating research suggests that heparanase may be a universal tumor-associated antigen (TAA). Several heparanase T-cell epitopes from humans and mice have already been identified. However, because of low immunogenicity, polypeptide vaccines usually have difficulty inducing effective antitumor immune responses in vivo. In this study, to increase the immunogenicity of polypeptide vaccines, we designed and synthesized two four-branch multiple antigenic peptides (MAP) on the basis of mouse heparanase (mHpa) T-cell epitopes (mHpa398 and mHpa519). The dendritic cells (DC) from mice bone marrow loaded with above MAP vaccines from heparanase were used to evaluate immune response against various tumor cell lines, compared with immune response to their corresponding linear peptides, ex vivo and in vivo. We further assessed IFN-γ release both in CD4+ T-cell–depleted and nondepleted mice. The results showed that effectors generated from DCs, loaded with MAP-vaccinated mice splenocytes, induced a stronger immune response against target cells expressing both heparanase and H-2Kb than did effectors generated from mice vaccinated with their corresponding linear peptides. Heparanase-specific CD8+ T-cell responses induced by MAP and linear peptide vaccination required synergy of CD4+ T cells. In addition, heparanse-derived MAP vaccines significantly inhibited the growth of B16 murine melanoma in C57BL/6 mice, while also increasing the survival rate of tumor-bearing mice. Our data suggest that MAP vaccines based on T-cell epitopes from heparanase are efficient immunogens for tumor immunotherapy. Mol Cancer Ther; 11(5); 1183–92. ©2012 AACR.