Chambers Benedict, Grufman Per, Fredriksson Vanoohi, Andersson Kenth, Roseboom Marjet, Laban Sandra, Camps Marcel, Wolpert Elisabeth Z, Wiertz Emmanuel J H J, Offringa Rienk, Ljunggren Hans-Gustaf, van Hall Thorbald
Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Cancer Res. 2007 Sep 15;67(18):8450-5. doi: 10.1158/0008-5472.CAN-07-1092.
A large proportion of human cancers show deficiencies in the MHC class I antigen-processing machinery. Such defects render tumors resistant to immune eradication by tumoricidal CTLs. We recently identified a unique population of CTL that selectively targets tumor immune-escape variants through recognition of MHC-presented peptides, termed TEIPP (T cell epitopes associated with impaired peptide processing), expressed on cells lacking functional TAP-peptide transporters. Previously, we showed that vaccination with TEIPP peptides mediates protection against TAP-deficient tumors. Here, we further explored the concept of TEIPP-targeted therapy using a dendritic cell (DC)-based cellular vaccine. Impairment of TAP function in DC induced the presentation of endogenous TEIPP antigens by MHC class I molecules, and immunization with these DCs protected mice against the outgrowth of TAP-deficient lymphomas and fibrosarcomas. Immune analysis of vaccinated mice revealed strong TEIPP-specific CTL responses, and a crucial role for CD8(+) cells in tumor resistance. Finally, we show that TEIPP antigens could be successfully induced in wild-type DC by introducing the viral TAP inhibitor UL49.5. Our results imply that immune intervention strategies with TAP-inhibited DC could be developed for the treatment of antigen processing-deficient cancers in humans.
很大一部分人类癌症显示出MHC I类抗原加工机制存在缺陷。这些缺陷使肿瘤对杀瘤性细胞毒性T淋巴细胞（CTL）的免疫清除产生抗性。我们最近鉴定出一种独特的CTL群体，其通过识别在缺乏功能性TAP-肽转运蛋白的细胞上表达的、被称为TEIPP（与肽加工受损相关的T细胞表位）的MHC呈递肽，选择性地靶向肿瘤免疫逃逸变体。此前，我们表明用TEIPP肽进行疫苗接种可介导对TAP缺陷型肿瘤的保护作用。在此，我们使用基于树突状细胞（DC）的细胞疫苗进一步探索TEIPP靶向治疗的概念。DC中TAP功能的受损导致MHC I类分子呈递内源性TEIPP抗原，用这些DC进行免疫可保护小鼠免受TAP缺陷型淋巴瘤和纤维肉瘤的生长。对接种疫苗小鼠的免疫分析揭示了强烈的TEIPP特异性CTL反应，以及CD8(+)细胞在肿瘤抗性中的关键作用。最后，我们表明通过引入病毒TAP抑制剂UL49.5可在野生型DC中成功诱导TEIPP抗原。我们的结果表明，可以开发用TAP抑制的DC进行免疫干预策略来治疗人类抗原加工缺陷型癌症。
