Enhanced efficacy of tumor cell vaccines transfected with secretable hsp70
Enhanced efficacy of tumor cell vaccines transfected with secretable hsp70
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DOI：
10.1158/0008-5472.can-03-2936
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发表时间：
2004-02-15
期刊：
影响因子：
11.2
通讯作者：
Melani, C
中科院分区：
文献类型：
--
作者：
Massa, C;Guiducci, C;Melani, C
肿瘤免疫治疗已经利用热休克蛋白质将抗原肽的前体分子陪伴到抗原呈递细胞并有效激活针对肿瘤相关抗原的免疫应答的能力。最常见的策略是基于从肿瘤细胞系或从肿瘤手术样品中纯化热休克蛋白-肽复合物用于体内施用。在这篇文章中，我们已经修改了小鼠诱导的hsp 70成分泌蛋白和工程肿瘤细胞分泌组成型与hsp 70蛋白相关的抗原库。体外研究表明，hsp 70从细胞质到分泌途径的重新定位并没有改变hsp 70与来自天然肿瘤相关抗原或模型抗原的肽相互作用的能力，并且抗原呈递细胞特异性地摄取分泌的hsp 70并将伴侣表位呈递给T细胞。体内研究表明，分泌hsp 70的肿瘤显示出增强的免疫原性，诱导强烈的特异性CTL应答。与携带亲本肿瘤的小鼠相比，注射hsp 70分泌肿瘤的小鼠显示出存活率增加和肿瘤摄取受损。超过70%的小鼠通过涉及T淋巴细胞和自然杀伤细胞的机制排斥分泌hsp 70的肿瘤细胞，在T淋巴细胞的情况下诱导记忆反应。此外，热休克蛋白70的分泌增加了肿瘤细胞疫苗的免疫原性潜力。
Tumor immunotherapy has exploited the ability of heat shock proteins to chaperone precursors of antigenic peptides to antigen-presenting cells and to activate efficiently an immune response against tumor-associated antigens. The most common strategy is based on the purification of heat shock protein-peptide complexes from tumor cell lines or from tumor surgical samples for in vivo administration. In this article, we have modified the murine-inducible hsp70 into a secreted protein and engineered tumor cells to secrete constitutively their antigenic repertoire associated with the hsp70 protein. In vitro studies showed that the relocalization of hsp70 from the cytoplasm to the secretory pathway did not modify the ability of hsp70 to interact with peptides derived either from natural tumor-associated antigens or model antigens, and that antigen-presenting cells specifically took up the secreted hsp70 and presented the chaperoned epitopes to T cells. In vivo studies showed that tumors secreting hsp70 displayed increased immunogenicity, with induction of a strong and specific CTL response. Mice injected with hsp70-secreting tumors showed increased survival and impaired tumor take compared with mice bearing parental tumors. More than 70% of mice rejected tumor cells secreting hsp70 through mechanisms that involve T lymphocytes and natural killer cells, with the induction of a memory response in the case of T lymphocytes. Moreover, hsp70 secretion increased the immunogenic potential of tumor cell vaccines.