Identification of a common HLA-A*0201-restricted epitope among SSX family members by mimicking altered peptide ligands strategy.
Identification of a common HLA-A*0201-restricted epitope among SSX family members by mimicking altered peptide ligands strategy.
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DOI：
10.1016/j.molimm.2008.01.014
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发表时间：
2008-05
影响因子：
3.6
通讯作者：
Yangdong He;L. Mao;Zhihua Lin;Yijing Deng;Yan Tang;M. Jiang;Wan-ling Li;Z. Jia;Jiangxue Wang;B. Ni;Yuzhang Wu
中科院分区：
文献类型：
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作者：
Yangdong He;L. Mao;Zhihua Lin;Yijing Deng;Yan Tang;M. Jiang;Wan-ling Li;Z. Jia;Jiangxue Wang;B. Ni;Yuzhang Wu
滑膜肉瘤X断点（SSX）基因家族包含9个成员。SSX蛋白是CT（癌症/睾丸）抗原，并且可以在许多肿瘤类型中表达。针对SSX蛋白的T细胞免疫应答可以在肿瘤患者和表达任何SSX的小鼠中检测到。筛选出优势保护性表位可能会改善这些自身CT抗原的低免疫原性。在此，我们预测了所有9个SSX家族成员的HLA-A*0201限制性表位，然后用表位分子建模、肽/HLA-A*0201亲和力和结合稳定性测定进行验证。我们从9个SSX成员中获得了4个具有高免疫原性评分的高度同源的候选表位，命名为P1，P4，P5和P6。4种候选物均能诱导强烈的表位特异性CTL免疫应答，但P4能诱导更多的产生γ干扰素（IFN-γ）的T细胞和杀伤更多靶细胞的CTL。4个表位诱导的CTL在体外对人PBMCs和HLA-A2.1/Kb转基因小鼠的相互靶点均有交叉杀伤作用，但P4的交叉杀伤作用优于其他表位。所有这些结果表明，P4可以以上级于其他候选物的方式诱导抗肿瘤免疫，并且可能是所有SSX表达肿瘤中的“共同”CTL表位。由于其在本文中记录的应答，P4在肽介导的免疫疗法中具有潜在的应用。
The synovial sarcoma X breakpoint (SSX) gene family contains nine members. The SSX proteins are CT (cancer/testis) antigens and can be expressed in many tumor types. T cell immune response against SSX protein can be detected in tumor patients and mice expressing any SSX. Screening predominant protective epitopes might improve the low immunogenicity against these “self” CT antigens. Herein, we predicted HLA-A*0201-restricted epitopes for all nine SSX family members, followed by validation with epitope molecular modeling, peptide/HLA-A*0201 affinity, and binding stability assays. We obtained four highly homologous candidate epitopes with the high immunogenicity scores designated P1, P4, P5 and P6, from the nine SSX members. Each of the four candidates could elicit strong epitope-specific CTL immune responses, but P4 could evoke more interferon γ (IFN-γ)-producing T cells and more potent CTLs that could lyse more target cells. Importantly, almost all of the four epitopes induced CTLs could cross-lyse the mutual targets both in vitro in human PBMCs and HLA-A2.1/Kbtransgenic mice, but P4 showed superiority to other epitopes in term of cross-cytolysis. All of these results demonstrate that P4 can induce anti-tumor immunity in a fashion superior to other candidates, and may be the “common” CTL epitope among all SSX-expressing tumors. Due to its documented responses herein, P4 has potential application in peptide-mediated immunotherapy.