Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen.
Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen.
复制标题
DOI：
--
复制
发表时间：
1996
期刊：
影响因子：
11.2
通讯作者：
Ken Y. Lin;F. Guarnieri;K. Staveley-O’Carroll;H. Levitsky;J. August;D. Pardoll;T. Wu
中科院分区：
文献类型：
--
作者：
Ken Y. Lin;F. Guarnieri;K. Staveley-O’Carroll;H. Levitsky;J. August;D. Pardoll;T. Wu
MHC II 类分子向 CD4+ T 细胞呈递抗原肽对于抗肿瘤免疫的产生至关重要。为了增强 MHC II 类抗原加工，我们将溶酶体相关膜蛋白 (LAMP-1) 的分选信号与细胞质/核人乳头状瘤病毒 (HPV-16) E7 抗原连接起来，创建嵌合体 (Sig/E7/LAMP-1)。此前，我们发现，与表达野生型 E7 的痘苗相比，用重组痘苗载体在体外和体内表达该嵌合体可将 E7 靶向内体和溶酶体区室，并增强 MHC II 类向 CD4+ T 细胞的呈递。在当前的研究中，我们测试了这些重组痘苗对 E7+ 肿瘤 TC-1 的体内保护作用，TC-1 源自与 HPV-16 E6 和 E7 以及 c-Ha-ras 癌基因共转化的 C57BL/6 小鼠的原代上皮细胞。所有接种 1 x 10(7) 空斑形成单位的野生型 E7 牛痘的小鼠在受到致瘤剂量的 TC-1 肿瘤细胞攻击时均显示出进行性肿瘤生长；相比之下，80% 的接种嵌合 Sig/E7/LAMP1 牛痘疫苗的小鼠在注射肿瘤后 3 个月仍保持无肿瘤状态。此外，用 Sig/E7/LAMP-1 牛痘疫苗治疗可以治愈患有小型 TC-1 肿瘤的小鼠，而野生型 E7 牛痘疫苗对这种已形成的肿瘤负荷没有效果。这些发现指出了表达未修饰肿瘤抗原的重组牛痘的治疗局限性。此外，他们证明，将胞质肿瘤抗原重新路由至内体/溶酶体区室的修饰可以极大地提高重组疫苗的体内治疗效力。
Presentation of antigenic peptides by MHC class II molecules to CD4+ T cells is critical to the generation of antitumor immunity. In an attempt to enhance MHC class II antigen processing, we linked the sorting signals of the lysosome-associated membrane protein (LAMP-1) to the cytoplasmic/nuclear human papilloma virus (HPV-16) E7 antigen, creating a chimera (Sig/E7/LAMP-1). Previously, we found that expression of this chimera in vitro and in vivo with a recombinant vaccinia vector targeted E7 to endosomal and lysosomal compartments and enhanced MHC class II presentation to CD4+ T cells compared to vaccinia expressing wild-type E7. In the current study, we tested these recombinant vaccinia for in vivo protection against an E7+ tumor, TC-1, which was derived from primary epithelial cells of C57BL/6 mice cotransformed with HPV-16 E6 and E7 and c-Ha-ras oncogenes. All mice vaccinated with 1 x 10(7) plaque-forming units of wild-type E7-vaccinia showed progressive tumor growth when challenged with a tumorigenic dose of TC-1 tumor cells; in contrast, 80% of mice vaccinated with the chimeric Sig/E7/LAMP1 vaccinia remained tumor free 3 months after tumor injection. Furthermore, treatment with the Sig/E7/LAMP-1 vaccinia vaccine cured mice with small established TC-1 tumors, whereas the wild-type E7-vaccinia showed no effect on this established tumor burden. These findings point out the therapeutic limitations of recombinant vaccinia expressing unmodified tumor antigens. Further, they demonstrate that modifications that reroute a cytosolic tumor antigen to the endosomal/lysosomal compartment can profoundly improve the in vivo therapeutic potency of recombinant vaccines.