Mossoba Miriam E, Walia Jagdeep S, Rasaiah Vanessa I, Buxhoeveden Nicole, Head Renee, Ying Chuyan, Foley Jason E, Bramson Jonathan L, Fowler Daniel H, Medin Jeffrey A
Department of Medical Biophysics, University of Toronto, Toronto, Ontario,Canada.
Mol Ther. 2008 Mar;16(3):607-17. doi: 10.1038/sj.mt.6300390. Epub 2008 Jan 8.
Gene therapy strategies may accelerate the development of prophylactic immunotherapy against cancer. We synthesized a lentiviral (LV) vector encoding a kinase-deficient form of erbB2 (erbB2tr) to transduce murine dendritic cells (DCs) efficiently. Murine erbB2 models a clinically relevant tumor-associated self-antigen; its human homolog (HER-2/neu) is overexpressed in breast cancer and in 80% of metastatic prostate cancers. Following one infection, approximately 47% of DCs overexpressed erbB2tr. To determine whether low doses of transduced DCs could protect mice from prostate cancer cells, we performed prime/boost vaccinations with 2 x 10(3) or 2 x 10(5) erbB2tr-transduced DCs. Six weeks after vaccination, mice were simultaneously bilaterally challenged with the aggressive RM-1 prostate cancer cell line and an erbB2tr-expressing variant (RM-1-erbB2tr). Whereas control mice developed both tumors, all recipients of 2 x 10(5) erbB2tr-transduced DCs developed only wild-type RM-1 tumors. One-third of mice vaccinated with just 2 x 10(3) erbB2tr-transduced DCs also demonstrated erbB2tr-specific tumor protection. Protection against RM-1-erbB2tr tumors was associated with sustained levels of anti-erbB2tr antibody production and also correlated with erbB2tr-specific Th1 cytokine secretion. Depletion of CD4(+), CD8(+), or natural killer (NK) cells prior to tumor challenge underscored their role in mediating tumor protection. We conclude that administration of DCs expressing a self-antigen through efficient LV-based gene transfer activates cellular and humoral immunity, protecting host animals against specific tumor challenge.
基因治疗策略可能会加速针对癌症的预防性免疫疗法的发展。我们合成了一种慢病毒（LV）载体，其编码一种激酶缺陷型的erbB2（erbB2tr），以有效地转导小鼠树突状细胞（DCs）。小鼠erbB2模拟一种临床相关的肿瘤相关自身抗原；其人类同源物（HER-2/neu）在乳腺癌和80%的转移性前列腺癌中过表达。一次感染后，约47%的DCs过表达erbB2tr。为了确定低剂量的转导DCs是否能保护小鼠免受前列腺癌细胞的侵害，我们用2×10³或2×10⁵个erbB2tr转导的DCs进行了初次/加强疫苗接种。接种六周后，小鼠同时双侧接种侵袭性RM-1前列腺癌细胞系和一种表达erbB2tr的变体（RM-1-erbB2tr）。对照小鼠长出了两种肿瘤，而所有接受2×10⁵个erbB2tr转导的DCs的小鼠只长出了野生型RM-1肿瘤。仅用2×10³个erbB2tr转导的DCs接种的小鼠中有三分之一也表现出erbB2tr特异性的肿瘤保护作用。对RM-1-erbB2tr肿瘤的保护与抗erbB2tr抗体产生的持续水平相关，也与erbB2tr特异性Th1细胞因子分泌相关。在肿瘤攻击前耗尽CD4⁺、CD8⁺或自然杀伤（NK）细胞突出了它们在介导肿瘤保护中的作用。我们得出结论，通过基于LV的高效基因转移给予表达自身抗原的DCs可激活细胞免疫和体液免疫，保护宿主动物免受特定肿瘤攻击。
