Aspartate-β-hydroxylase induces epitope-specific T cell responses in hepatocellular carcinoma.
Aspartate-β-hydroxylase induces epitope-specific T cell responses in hepatocellular carcinoma.
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DOI：
10.1016/j.vaccine.2015.01.037
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发表时间：
2015-03-03
期刊：
影响因子：
5.5
通讯作者：
Wands JR
中科院分区：
文献类型：
--
作者：
Tomimaru Y;Mishra S;Safran H;Charpentier KP;Martin W;De Groot AS;Gregory SH;Wands JR
肝细胞癌（HCC）复发率高，预后差。天冬氨酸-β-羟化酶（ASPH）是一种高度保守的跨膜蛋白，在HCC中过度表达并促进恶性表型。ASPH蛋白衍生的HLA I类和II类肽产生抗原特异性CD4+和CD8+免疫应答的能力尚不清楚。因此，这些研究旨在确定基于肽的候选疫苗所需的表位特异性成分。由HCC患者外周血单个核细胞（PBMCs）产生的单核细胞来源的树突状细胞（dc）装载ASPH蛋白。辅助CD4+ T细胞和CD8+细胞毒性T淋巴细胞（ctl）与dc共孵育；用流式细胞术分析T细胞活化情况。利用免疫信息学工具预测HLA I类和ii类限制性ASPH序列，并合成相应的肽段。采用IFN-γ ELISpot法测定人外周血单核细胞各肽的免疫原性。负载ASPH蛋白的dc可激活来自HCC患者的PBMC群体中的CD4+和CD8+ T细胞。此外，预测的HLA I类和ii类限制性ASPH肽具有显著的免疫原性。来源于ASPH的HLA I类和ii类限制性肽均可诱导HCC中的T细胞活化。我们观察到，在HCC患者中，ASPH蛋白和相关肽具有高度的免疫原性，并产生产生抗肿瘤活性所需的细胞免疫反应类型。
Hepatocellular carcinoma (HCC) has a poor prognosis due to high recurrence rate. Aspartate-β-hydroxylase (ASPH) is a highly conserved transmembrane protein, which is over expressed in HCC and promotes a malignant phenotype. The capability of ASPH protein-derived HLA Class I and II peptides to generate antigen specific CD4+ and CD8+ immune responses is unknown. Therefore, these studies aim to define the epitope specific components required for a peptide based candidate vaccine. Monocyte-derived dendritic cells (DCs) generated from the peripheral blood mononuclear cells (PBMCs) of HCC patients were loaded with ASPH protein. Helper CD4+ T cells and CD8+ cytotoxic T lymphocytes (CTLs) were co-incubated with the DCs; T cell activation was evaluated by flow cytometric analysis. Immunoinformatics tools were used to predict HLA class I- and class II-restricted ASPH sequences, and the corresponding peptides were synthesized. The immunogenicity of each peptide in cultures of human PBMCs was determined by IFN-γ ELISpot assay. ASPH protein-loaded DCs activated both CD4+ and CD8+ T cells contained within the PBMC population derived from HCC patients. Furthermore, the predicted HLA class I- and class II-restricted ASPH peptides were significantly immunogenic. Both HLA class I- and class II-restricted peptides derived from ASPH induce T cell activation in HCC. We observed that ASPH protein and related peptides were highly immunogenic in patients with HCC and produce the type of cellular immune responses required for generation of anti-tumor activity.
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