Commissariat à l'Energie Atomique-Saclay, Institut de Biologie et Technologies, Service d'Ingénierie Moléculaire des Protéines, Gif-sur-Yvette, France.
J Immunol. 2010 Jul 1;185(1):418-23. doi: 10.4049/jimmunol.0901014. Epub 2010 May 28.
The angiogenic factor Midkine (MDK) is overexpressed in various human malignant tumors, although its expression is low or undetectable in normal adult tissues. Its expression in tumors and its detection in plasma have been associated with poor disease outcome, whereas its blockade was found to contribute to tumor regression. By weekly stimulation of T lymphocytes harvested in HLA-A2 healthy donors, we derived CD8 T cell lines specific for several MDK peptides. The T cell response was mostly dominated by two nonamer peptides localized in the signal peptide and in the C-terminal part of the protein, as assessed by IFN-gamma ELISPOT and HLA-A2 tetramer labeling. Peptide-specific T cell lines recognized cells transfected with an MDK-encoded plasmid and tumor cell lines naturally expressing the MDK protein, but not untransfected cells. T cell presentation of the two MDK epitopes was found to be TAP dependent. Experiments performed in HLA-A2 transgenic mice demonstrated the capacity of the two identified CD8 T cell epitopes to elicit a cytotoxic response. Altogether, our data show that the secreted MDK protein is a candidate vaccine for multiple cancers.
血管生成因子中期因子（MDK）在各种人类恶性肿瘤中过度表达，尽管其在正常成人组织中的表达水平较低或无法检测到。其在肿瘤中的表达及其在血浆中的检测与疾病预后不良相关，而其阻断被发现有助于肿瘤消退。通过每周刺激 HLA-A2 健康供体中采集的 T 淋巴细胞，我们衍生出针对多种 MDK 肽的 CD8 T 细胞系。通过 IFN-γ ELISPOT 和 HLA-A2 四聚体标记评估，T 细胞反应主要由位于信号肽和蛋白质 C 末端的两个非肽决定，该反应主要由两个非肽决定，由位于信号肽和蛋白质 C 末端的两个非肽决定。鉴定的两个 CD8 T 细胞表位的 T 细胞呈递被发现依赖于 TAP。在 HLA-A2 转基因小鼠中进行的实验证明了这两个鉴定的 CD8 T 细胞表位具有引发细胞毒性反应的能力。总的来说，我们的数据表明分泌的 MDK 蛋白是多种癌症的候选疫苗。
