Enhanced immunogenicity of heat shock protein 70 peptide complexes from dendritic cell-tumor fusion cells
Enhanced immunogenicity of heat shock protein 70 peptide complexes from dendritic cell-tumor fusion cells
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DOI：
10.4049/jimmunol.177.9.5946
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发表时间：
2006-11-01
影响因子：
4.4
通讯作者：
Gong, Jianlin
中科院分区：
文献类型：
--
作者：
Enomoto, Yutaka;Bharti, Ajit;Gong, Jianlin
我们已经开发出一种基于分子伴侣的肿瘤疫苗，可以逆转癌细胞的免疫耐受。从树突状细胞（DC）和肿瘤细胞融合物中提取的热休克蛋白（HSP） 70 （HSP70.PC-F）具有刺激DC成熟和T细胞增殖等优于肿瘤细胞的特性。更重要的是，HSP70小鼠免疫。PC-F导致T细胞介导的免疫应答，包括CD8 T细胞的显著增加和效应T细胞和记忆T细胞的诱导，这些T细胞能够打破T细胞对非突变肿瘤Ag的无反应性，并为小鼠抵抗肿瘤细胞的攻击提供保护。相比之下，用肿瘤细胞衍生的HSP70-PC接种疫苗对这种非突变肿瘤Ag的免疫反应是沉默的。HSP70。PC-F复合物与来自肿瘤细胞的复合物在许多关键方面有所不同，最值得注意的是，它们与免疫肽的关联增强。此外，分子伴侣HSP90被发现与HSP70相关。通过共沉淀法显示PC-F，表明两种伴侣携带抗原肽库的能力增加。值得注意的是，HSP70激活DC。PC-F依赖于完整的MyD88基因的存在，这表明TLR信号在DC激活和T细胞刺激中起作用。这些实验表明，来自dc -肿瘤融合细胞的hsp70肽复合物（PC）具有增强的免疫原性，因此构成了基于伴侣蛋白的肿瘤疫苗的改进配方。
We have developed a molecular chaperone-based tumor vaccine that reverses the immune tolerance of cancer cells. Heat shock protein (HSP) 70 extracted from fusions of dendritic (DC) and tumor cells (HSP70.PC-F) possess superior properties such as stimulation of DC maturation and T cell proliferation over its counterpart from tumor cells. More importantly, immunization of mice with HSP70.PC-F resulted in a T cell-mediated immune response including significant increase of CD8 T cells and induction of the effector and memory T cells that was able to break T cell unresponsiveness to a nonmutated tumor Ag and provide protection of mice against challenge with tumor cells. By contrast, the immune response to vaccination with HSP70-PC derived from tumor cells is muted against such nonmutated tumor Ag. HSP70.PC-F complexes differed from those derived from tumor cells in a number of key manners, most notably, enhanced association with immunologic peptides. In addition, the molecular chaperone HSP90 was found to be associated with HSP70.PC-F as indicated by coirnmunoprecipitation, suggesting ability to carry an increased repertoire of antigenic peptides by the two chaperones. Significantly, activation of DC by HSP70.PC-F was dependent on the presence of an intact MyD88 gene, suggesting a role for TLR signaling in DC activation and T cell stimulation. These experiments indicate that HSP70-peptide complexes (PC) derived from DC-tumor fusion cells have increased their immunogenicity and therefore constitute an improved formulation of chaperone protein-based tumor vaccine.