Active Immunotherapy Combined With Blockade of a Coinhibitory Pathway Achieves Regression of Large Tumor Masses in Cancer-prone Mice
Active Immunotherapy Combined With Blockade of a Coinhibitory Pathway Achieves Regression of Large Tumor Masses in Cancer-prone Mice
复制标题
DOI：
10.1038/mt.2011.88
复制
发表时间：
2011-09-01
影响因子：
12.4
通讯作者：
Ertl, Hildegund C. J.
中科院分区：
文献类型：
--
作者：
Lasaro, Marcio O.;Sazanovich, Marina;Ertl, Hildegund C. J.
旨在扩增肿瘤特异性CD 8（+）T细胞的疫苗在癌症患者中产生了令人失望的结果，尽管它们在可移植肿瘤小鼠模型中显示出有效性。使用更忠实地模拟进展中的癌症及其免疫抑制微环境的系统，我们在这里表明，在转基因小鼠中，由于甲状腺内HPV-16 E7的表达而逐渐发展为腺癌，表达E7的高免疫原性疫苗仅诱导低E7特异性CD 8（+）T细胞应答，这不能影响肿瘤的大小。相反，表达与单纯疱疹病毒（HSV）-1糖蛋白D（gD）融合的E7的相同类型的疫苗（共抑制性B-和T-淋巴细胞衰减因子（BTLA）/CD 160-疱疹病毒进入介体（HVEM）途径的拮抗剂）刺激有效的E7特异性CD 8（+）T细胞应答，其可通过重复接种来增强，导致所有小鼠中即使是较大的肿瘤块也会初步消退，其中一半以上的肿瘤块持续消退。这些结果表明，主动免疫伴随通过HSV-1 gD阻断免疫抑制性HVEM-BTLA/CD 160途径可导致持续的肿瘤消退。
Vaccines that aim to expand tumor-specific CD8(+) T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we here show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8(+) T-cell responses, which fail to affect the size of the tumors. In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B- and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8(+) T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression.