Laboratory of Cellular Physiology and Immunology and Chris Browne Center of Immunology and Immune Disease, The Rockefeller University, 1230 York Ave, New York, NY 10065, USA.
Breast Cancer Res. 2012 Mar 7;14(2):R39. doi: 10.1186/bcr3135.
Given their relative simplicity of manufacture and ability to be injected repeatedly, vaccines in a protein format are attractive for breast and other cancers. However, soluble human epidermal growth factor receptor (HER2)/neu protein as a vaccine has not been immunogenic. When protein is directly targeted to antigen uptake receptors, such as DEC205 (DEC), efficient processing and presentation of antigen take place. The aim of this study was to determine the immunogenicity of a HER2 protein vaccine that directly targets to DEC+ dendritic cells (DCs) in a mouse breast cancer model.
We genetically engineered the HER2 extracellular domain into a monoclonal antibody specific for DEC (DEC-HER2). Mice of various genetic backgrounds were immunized with DEC-HER2 in combination with DC maturation stimuli (poly IC ± CD40 Ab). Vaccine-induced T cell immunity was determined by analyzing the ability of CD4+/CD8+ T cell to produce interferon (IFN)-gamma and proliferate upon antigen rechallenge. Sera were assessed for the presence of antigen specific antibody (Ab). For vaccine efficacy, FVB/N mice were immunized with DEC-HER2 in combination with poly IC and protection against neu-expressing mammary tumors was assessed. Protection mechanisms and tumor-specific T cell responses were also evaluated.
We demonstrate that DEC-HER2 fusion mAb, but not Ctrl Ig-HER2, elicits strong, broad and multifunctional CD4+ T cell immunity, CD8+ T cell responses, and humoral immunity specific for HER2 antigen. Cross-reactivity to rat neu protein was also observed. Importantly, mice xeno-primed with DEC-HER2 were protected from a neu-expressing mammary tumor challenge. Both CD4+ and CD8+ T cells mediated the tumor protection. Robust anti-tumor T cell immunity was detected in tumor protected mice.
Immunization of mice with HER2 protein vaccine targeting DEC+ DCs in vivo induced high levels of T- and B-cell immunity. Non-targeted HER2 protein was poorly immunogenic for CD4+ and CD8+ T cells. This vaccination approach provided long-term survival benefit for mice challenged with neu-expressing tumor following as little as 2.7 μg of HER2 protein incorporated in the vaccine. Vaccine-induced CD4+ and CD8+ T cells were both essential for tumor protection. This immunization strategy demonstrates great potential towards the development of vaccines for breast cancer patients.
鉴于其制造相对简单且能够反复注射，蛋白质形式的疫苗对于乳腺癌和其他癌症具有吸引力。然而，可溶性人表皮生长因子受体（HER2）/neu 蛋白作为疫苗没有免疫原性。当蛋白质直接靶向抗原摄取受体（如 DEC205（DEC））时，抗原的有效加工和呈递就会发生。本研究旨在确定直接针对乳腺癌模型中 DEC+树突状细胞（DC）的 HER2 蛋白疫苗的免疫原性。
我们将 HER2 细胞外结构域基因工程改造到针对 DEC 的单克隆抗体（DEC-HER2）中。用 DEC-HER2 与 DC 成熟刺激物（poly IC ± CD40 Ab）组合免疫各种遗传背景的小鼠。通过分析 CD4+/CD8+T 细胞在抗原再挑战时产生干扰素（IFN）-γ和增殖的能力来确定疫苗诱导的 T 细胞免疫。评估血清中存在的抗原特异性抗体（Ab）。为了评估疫苗的疗效，用 DEC-HER2 与 poly IC 组合免疫 FVB/N 小鼠，并评估对表达 neu 的乳腺肿瘤的保护作用。还评估了保护机制和肿瘤特异性 T 细胞反应。
我们证明，DEC-HER2 融合 mAb，但不是对照 Ig-HER2，可引发强烈、广泛和多功能的 CD4+T 细胞免疫、CD8+T 细胞反应和针对 HER2 抗原的体液免疫。还观察到对大鼠 neu 蛋白的交叉反应性。重要的是，用 DEC-HER2 异源 primed 的小鼠受到表达 neu 的乳腺肿瘤挑战的保护。CD4+和 CD8+T 细胞均介导肿瘤保护。在受保护的肿瘤小鼠中检测到强大的抗肿瘤 T 细胞免疫。
体内用针对 DEC+DC 的 HER2 蛋白疫苗免疫小鼠可诱导高水平的 T 细胞和 B 细胞免疫。未靶向的 HER2 蛋白对 CD4+和 CD8+T 细胞的免疫原性较差。这种疫苗接种方法在疫苗中仅包含 2.7 μg 左右的 HER2 蛋白的情况下，为接受表达 neu 的肿瘤挑战的小鼠提供了长期的生存获益。疫苗诱导的 CD4+和 CD8+T 细胞对于肿瘤保护都是必不可少的。这种免疫策略为开发乳腺癌患者的疫苗提供了巨大潜力。
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