Felicetti P, Mennecozzi M, Barucca A, Montgomery S, Orlandi F, Manova K, Houghton A N, Gregor P D, Concetti A, Venanzi F M
Swim Across America Laboratory of Tumor Immunology, Memorial Sloan-Kettering Cancer Center, New York, USA.
Cytotherapy. 2007;9(1):23-34. doi: 10.1080/14653240601048369.
We have previously shown that xenogeneic DNA vaccines encoding rat neu and melanosomal differentiation Ag induce tumor immunity. Others have developed vaccines targeting tumor neovasculature. Tumor endothelial marker 8 (TEM8) is expressed in the neovasculature of human tumors, and in the mouse melanoma B16, but its expression is limited in normal adult tissues. We describe a DNA vaccine combining xenogeneic tumor Ag and TEM8.
In-situ hybridization was used to detect TEM8 RNA in mouse tumors. Mice transgenic for the rat neu proto-oncogene were immunized with DNA vaccines encoding TEM8 and the extracellular domain of rat neu and challenged with the 233-VSGA1 breast cancer cell line. In parallel experiments, C57BL/6 mice were immunized with TEM8 and human tyrosinase-related protein 1 (hTYRP1/hgp75) and challenged with B16F10 melanoma.
TEM8 was expressed in the stroma of transplantable mouse breast and melanoma tumors. In both model systems, TEM8 DNA had no activity as a single agent but significantly enhanced the anti-tumor immunity of neu and hTYRP1/hgp75 DNA vaccines when given in concert. The observed synergy was dependent upon CD8+ T cells, as depletion of this cell population just prior to tumor challenge obviated the effect of the TEM8 vaccine in both tumor models.
A local immune response to TEM8 may increase inflammation or tumor necrosis within the tumor, resulting in improved Ag presentation of HER2/neu and hTYRP1/hgp75. Alternatively, TEM8 expression in host APC may alter T-cell interactions or homing. In this way, TEM8 may act more as an adjuvant than an immunologic target.
我们之前已经表明，编码大鼠neu和黑素体分化抗原的异种DNA疫苗可诱导肿瘤免疫。其他人已经开发出针对肿瘤新生血管的疫苗。肿瘤内皮标志物8（TEM8）在人类肿瘤的新生血管中表达，在小鼠黑色素瘤B16中也有表达，但其在正常成人组织中的表达有限。我们描述了一种结合异种肿瘤抗原和TEM8的DNA疫苗。
采用原位杂交检测小鼠肿瘤中TEM8 RNA。用编码TEM8和大鼠neu细胞外结构域的DNA疫苗免疫大鼠neu原癌基因转基因小鼠，并用233-VSGA1乳腺癌细胞系进行攻击。在平行实验中，用TEM8和人酪氨酸酶相关蛋白1（hTYRP1/hgp75）免疫C57BL/6小鼠，并用B16F10黑色素瘤进行攻击。
TEM8在可移植的小鼠乳腺和黑色素瘤肿瘤的基质中表达。在两个模型系统中，TEM8 DNA作为单一药物没有活性，但与neu和hTYRP1/hgp75 DNA疫苗联合使用时，可显著增强抗肿瘤免疫力。观察到的协同作用依赖于CD8 + T细胞，因为在肿瘤攻击前耗尽该细胞群消除了TEM8疫苗在两种肿瘤模型中的作用。
对TEM8的局部免疫反应可能会增加肿瘤内的炎症或肿瘤坏死，从而改善HER2/neu和hTYRP1/hgp75的抗原呈递。或者，宿主APC中TEM8的表达可能会改变T细胞相互作用或归巢。通过这种方式，TEM8可能更多地作为佐剂而不是免疫靶点发挥作用。
