Department of General, Thoracic, Vascular and Transplantation Surgery, Section Molecular Oncology and Immunotherapy, University of Rostock, Germany.
Cancer Immunol Immunother. 2012 Jul;61(7):1093-100. doi: 10.1007/s00262-011-1183-3. Epub 2011 Dec 21.
Our genome consists to about 8% of human endogenous retroviral (HERV) sequences. These HERVs have been discussed to be linked to human diseases for decades. Recently, a detailed analysis of a HERV-H sequence located on chromosome Xp22.3 revealed a strong expression in a subset of gastrointestinal cancers whereas expression in normal tissues and in other cancer entities was low. In the present study, we used the reverse immunology approach to test the immunological potential of this HERV-H ORF on Xp22.3. A total of ten peptides displaying HLA-A2.1-binding motifs were selected from the predicted env protein sequence. Stimulation of peripheral T cells with retroviral peptides (RVPs) presented by autologous antigen-presenting cells clearly resulted in sustained proliferation of predominantly CD8(+) T cells. High numbers of IFN-γ-secreting T cells were detectable after several weekly stimulations with RVP mixes. Reactivity observed in RVP-Mix-stimulated cultures was attributable to RVP03, RVP09 and to a lower extend to RVP08, suggesting those to be highly immunogenic epitopes. Besides killing of RVP-loaded target cells, up to 40% specific lysis of colorectal carcinoma cell lines endogenously expressing this HERV-H Xp22.3 ORF was achieved. These data demonstrate that human T cells can be sensitized toward HERV peptides and moreover posses a high lytic potential toward HERV-H expressing CRC cells. Additionally, these data hint toward endogenous ENV protein expression followed by proteasomal degradation and presentation in the context of HLA molecules. Finally, our data strengthen the view that HERV-encoded sequences should be considered as a new class of tumor-specific antigens.
我们的基因组约有 8%是人类内源性逆转录病毒（HERV）序列。这些 HERV 已经被讨论了几十年，与人类疾病有关。最近，对位于 Xp22.3 染色体上的 HERV-H 序列的详细分析表明，它在胃肠道癌症的一个亚群中强烈表达，而在正常组织和其他癌症实体中的表达较低。在本研究中，我们使用反向免疫学方法来测试 Xp22.3 上的这个 HERV-H ORF 的免疫潜力。从预测的 env 蛋白序列中选择了十个显示 HLA-A2.1 结合基序的肽。用自体抗原呈递细胞呈递的逆转录病毒肽（RVPs）刺激外周 T 细胞，明显导致主要是 CD8+T 细胞的持续增殖。在用 RVP 混合物进行几次每周刺激后，可检测到大量 IFN-γ 分泌的 T 细胞。在 RVP-Mix 刺激的培养物中观察到的反应归因于 RVP03、RVP09，以及较低程度的 RVP08，表明它们是高度免疫原性的表位。除了杀伤负载 RVP 的靶细胞外，还可以实现对天然表达该 HERV-H Xp22.3 ORF 的结直肠癌细胞系高达 40%的特异性溶解。这些数据表明，人类 T 细胞可以对 HERV 肽产生敏感性，并且对表达 HERV-H 的 CRC 细胞具有高裂解潜力。此外，这些数据表明存在内源性 ENV 蛋白表达，随后进行蛋白酶体降解，并在 HLA 分子的背景下呈递。最后，我们的数据强化了这样一种观点，即 HERV 编码的序列应被视为一类新的肿瘤特异性抗原。
