Wang Qun, Cao Wei, Yang Zhi-Gang, Zhao Guang-Fa
Department of Surgical Oncology, Shanghai Shidong Hospital Shanghai, China.
Department of Oncology, Fudan University Shanghai Cancer Center Shanghai, China.
Int J Clin Exp Med. 2015 Oct 15;8(10):17565-77. eCollection 2015.
Anti-CD11c antibodies target to the CD11c receptor that mediates antigen presentation to T cells by dendritic cells (DCs). To exploit these properties for immunization purposes, we obtained DC-targeting DNA vaccines by fusing tumor-associated antigen HER2/neu ectodomain to single chain antibody fragment (scFv) from N418 (scFv(N418)), a monoclonal antibody binding the mouse DC-restricted surface molecule CD11c, and explored its antitumoral efficacy and underlying mechanisms in mouse breast cancer models.
Induction of humoral and cellular immune responses and antitumoral activity of the DNA vaccines were tested in transplantable HER2/neu-expressing murine tumor models and in transgenic BALB-neuT mice developing spontaneous Neu-driven mammary carcinomas.
Upon injection of the breast tumor cell line D2F2/E2 (stably expressing human wild-type HER2), scFv(N418)-HER2 immunized mice were protected against tumor growth. Even more important for clinical applications, we were able to substantially slow the growth of implanted D2F2/E2 cells by injection of scFv(N418)-HER2 conjugates into tumor bearing hosts. The existing tumors were eradicated by treatment with scFv(N418)-HER2 combined with low-dose cyclophosphamide (CTX), which can make a temporary regulatory T cells (Treg) depletion. What's more, in combination with the low-dose CTX, vaccination with scFv(N418)-neu significantly retarded the development of spontaneous mammary carcinomas in transgenic BALB-neuT mice.
Our results show that DNA vaccine which targeting of dendritic cells in situ by the means of antibody-antigen conjugates may be a novel way to induce long-lasting antitumor immunity.
抗CD11c抗体靶向CD11c受体，该受体介导树突状细胞（DCs）向T细胞呈递抗原。为了利用这些特性进行免疫，我们通过将肿瘤相关抗原HER2/neu胞外结构域与来自N418的单链抗体片段（scFv）（scFv(N418)）融合，获得了靶向DC的DNA疫苗，N418是一种结合小鼠DC限制性表面分子CD11c的单克隆抗体，并在小鼠乳腺癌模型中探索了其抗肿瘤疗效及潜在机制。
在可移植的表达HER2/neu的小鼠肿瘤模型和发生自发性Neu驱动的乳腺癌的转基因BALB-neuT小鼠中，测试DNA疫苗诱导体液免疫和细胞免疫反应以及抗肿瘤活性。
注射乳腺肿瘤细胞系D2F2/E2（稳定表达人野生型HER2）后，scFv(N418)-HER2免疫的小鼠可免受肿瘤生长。对临床应用更重要的是，通过向荷瘤宿主注射scFv(N418)-HER2偶联物，我们能够显著减缓植入的D2F2/E2细胞的生长。用scFv(N418)-HER2联合低剂量环磷酰胺（CTX）治疗可根除现有肿瘤，CTX可使调节性T细胞（Treg）暂时耗竭。此外，与低剂量CTX联合使用时，用scFv(N418)-neu疫苗接种可显著延缓转基因BALB-neuT小鼠自发性乳腺癌的发展。
我们的结果表明，通过抗体-抗原偶联物原位靶向树突状细胞的DNA疫苗可能是诱导持久抗肿瘤免疫的一种新方法。
